Microsoft PowerPoint - 2) Diethylene glycol.ppt06/3/2010
CHEMICAL PROPERTIES OF DIETHYLENE GLYCOL (DEG)
C4H10O3, O(CH2CH2OH)2 Glycol, CAS No. 111-46-6 Molecular weight 106.12 g/mol Melting point -6.5°C, boiling point 245°C, vapor pressure <0.01mmHg at 25°C Clear colourless, viscous, odorless, sweet-tasting hydroscopic liquid Synonyms: "2, 2' -oxybisethanol", "2, 2' -oxybisethanol", "2, 2' -oxydiethanol", "2, 2' -oxydiethanol", "bis(2-hydroxyethyl) ether", diglycol, "diglycol stearate", "ethylene diglycol", "glycol ether", "glycol ethyl ether", "dihydroxydiethyl ether", "2-hydroxyethyl ether", "2-hydroxyethyl ether", "2, 2' -oxidiglycol ether", "2, 2' -oxidiglycol ether", "3- oxapentane-1, 5-diol", "3-oxapentane-1, 5-diol", "3-oxa-1, 5- pentanediol", "3-oxa-1, 5-pentanediol", "beta, beta' - dihydroxydiethyl
The physical properties of DEG make it an excellent counterfeit for pharmaceutical-grade glycerine or propylene glycol
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PRODUCT USE Production of polyurethane and unsaturated polyester resins,
triethylene glycol Textile softener Antifreeze Solvent for printing inks Plasticizer for cork, adhesives, paper and packaging materials Petroleum solvent extraction Dehydration of natural gas, plasticizers, and surfactants Humectant for tobacco, casein, synthetic sponges, paper products Has been used as an illegal additive for sweetening of wine. US FDA advises cosmetic preparations are to contain less than 10% DEG
TOXICITY OF DEG Not well established Oral LD50 ~4.9 g/Kg (rabbits) to 28.2 g/Kg (mice) Low hazard with industrial use due to its low vapor pressure and low dermal penetration In sulfanilemide elixir with DEG, the average fatal dose to human is 0.5-5g/Kg ~ 1.3ml/Kg (for children) Lethal dose in adult ~1ml/Kg
One suggests >10 mg in children or >30 mg if adult should be admitted and given antidote
Raymond RW. Glycol ethers and diethylene glycol. In: Ford MD, Delaney KA, Ling LJ, Erickson T, eds. Clinical Toxicology. Philadelphia, PA: Saunders Company; 2001:774–781.
DIETHYLENE GLYCOL
Renal failure 105 deaths
Produced sulfanilamide tablets
Problem sulfanilamide insoluble in Ethanol
CHIEF CHEMIST
10% sulfanilamide 72% diethylene glycol 16% water Flavor, raspberry extract, saccharine, amaranth and caramel
“Elixir sulfanilamide”
No Toxicity Testing
No Clinical Trials
“Throwing drugs together and if they did not explode, they were placed on sale.” FDA Agent’s description of Company’s drug development strategy
SEPTEMBER 1937 240 gallons of elixir sulfanilamide
manufactured 1304 shipments throughout the US Major distribution to Tulsa, OK
2ND OCTOBER 1937
“6 patients dead from renal failure unexpectedly after ingestion Elixir Sulfanilamide stop request composition of the elixir.”
Sulfanilamide—a warning (Editorial). JAMA. 1937; 109:1128
HAVE YOU TRIED IT? AMA never heard of this preparation
Telegraphed the company requesting composition
Chief Chemist self administered small amount to show confidence in his product
Told AMA -> No adverse effects
MID OCTOBER 1937 Telegraph from the company to AMA “Please wire collect by Western Union
suggestion for antidote and treatment following use of Elixir Sulfanilamide”
AMA to the company “Antidote for Elixir Sulfanilamide –not
known. Treatment presumably symptomatic”
LATE OCTOBER 1937 News of Tulsa deaths reached Washington
353 patients received Elixir Sulfanilamide over a 4 week period 105 deaths (case fatality rate of 30%) 34 children & 71 adults died
GI symptoms prevented most of the survivors from ingesting enough
NOVEMBER 1937 – CONGRESS TO THE RESCUE Senator Royal Copeland (R-MI, D NY)
1938 Food Drug and Cosmetic Act (1) New Drug Application to demonstrate product safety – concept of animal/human testing before interstate shipping (2) formula must be disclosed (3) Directions for use and precautions on prescription
CONSUMER PRODUCTS CONTAMINATED WITH DEG
Austrian wine 1985 “Made in China” Toothpaste 2007
GUANGDONG PROVINCE HOSP 2006
A tailor falsified his license and laboratory analysis reports.
He declared that after making the first order of counterfeit syrup, he swallowed some of it. Once verifying that he was fine, he shipped it to the company in 2005. Some time later, he found a reference to diethylene glycol in a chemical book. After manufacturing a second batch of syrup containing diethylene glycol for the company, no taste-test was performed. The counterfeit syrup ended in ampules of Amillarisin A
In April 2006, the Guangdong Province Hospital of Guangzhou began administering Amillarisin A to their patients. Soon thereafter, patients died after receiving the medication. He was caught and the company was shut down by the authorities.
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PANAMA 2006 -Sept 2006, many patients presented with GBS symptoms and signs, respi failure But anuria. 50% died. ? Infectious dis -half of the pts had DM, HT, and had been given lisinopril
-2 patients admitted to the hospital with heart dis took lisinopril + cough syrup, then developed ARF -An epidemiologist from CDC tested & proved it was tainted with DEG
-Traced the source of the glycerine, and turned out the 46 barrels of labelled “glycerine 99.5%” was counterfeited with DEG
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WORLDWIDE TOOTHPASTE INCIDENT 2007
In May 2007, a Panamanian discovered a 59% toothpaste that was labeled containing DEG. Panamanian officials traced the toothpaste to a local company. In fact, the company bought the product in China and had already re-exported toothpaste to Costa Rica, Dominican Republic and Haiti, making Panama kick off a local warning.
In June 1, 2007, the FDA warned consumers to avoid toothpaste from China
20076110.21 7.5
In July 2007, England detected a counterfeit toothpaste on sale at a car boot in Derbyshire. Soon, authorities in Belize, Canada, Mozambique, Saudi Arabia, New Zealand, Spain, Italy, Japan, Ireland and an Indianapolis, Indiana US hotel supplier that distributed Chinese toothpaste in Barbados, Belgium, Bermuda, Britain, Canada, Dominican Republic, France, Germany, Ireland, Italy, Mexico, Spain, Switzerland, Turks and Caicos, the United Arab Emirates and United States were also recalling Chinese made toothpaste
CONSUMER PRODUCTS CONTAMINATED WITH DEG
CONSUMER PRODUCTS CONTAMINATED WITH DEG
EXTENT OF THE PROBLEM - FACTS
In Panama, a Diethylene glycol (DEG) poisoning killed 30 people. In this case, a material labeled as glycerin purportedly contained a mixture of 1% glycerol, 25% DEG and 75% unknown material.
Same DEG contaminated syrup killed 30 children in India in 1998
Same problem occurred in Haiti, 1995 because of DEG contaminated acetaminophen, 109 children had renal failure; 89 of them died.
MECHANISM OF CONTAMINATION Errors common to previous DEG-associated large-scale poisoning events:
1) use of unknown or unapproved raw material suppliers for propylene glycol
2) lack of certificates of analysis from suppliers to certify the ingredient’s identity and purity
3) failure to perform propylene glycol identity testing
4) failure to analyze finished product for DEG 5) failure to track the distribution of finished
product
Age of affected No of exposure/ death
1937 USA DEG Sulfanilamide (72%) 30% children 105 / 353
1969 S Africa Propylene glycol OTC Sedatives (Pronap & Plaxim)
Children 7
- 5
1985 Netherlands Austrian Wine (1000 parts per million of DEG)
Adults
Adults 14
1990-2 Bangladesh Propylene glycol / glycerol
Acetaminophen Children 236 / 339
1996 Haiti Glycerine Acetaminophen (24%) Children 101 / 109
1998 1998
Children 33 / 36 8
-
2006 Armillarisin-A - 12
RISK ASSESSMENT ( SCORE ) Severity score category: 5 (Severe)
Count Score category: 1 (Low)
Occurrence Score category: 1
Relevance Score category: 3 (Definite)
In summary, a total score of 10 is given, which indicate its high poisoning risk.
EXPOSURE ROUTES AND PATHWAYS
Accidental: epidemic (DEG was substituted in pharmaceutical preparations for the most expensive glycols or glycerine)
Intentional: suicidal attempt by ingesting DEG or DEG- based brake fluids, or canned fuel for recreational purposes as an alcohol substitute
TOXICOKINETICS OF DEG - ABSORPTION
Oral doses in rats are rapidly and completely absorbed with peak plasma conc achieved within 24-120 min
Pulmonary absorption depends on vapor pressure
~10% of dermal applied DEG is absorbed by rats if exposure in a large area (50mg/12cm2) by 72 hrs
TOXICOKINETICS OF DEG – DISTRIBUTION
Widely distributed Kidney > brain > spleen > liver > muscle > fat Also cross BBB (narcotic effects is observed within 20 min following ingestion in rats) VD ~ 1L/Kg
Alcohol Volume of Distribution(L/kg) Half life(h) Route of Elimination(%) Alone With ethanol Liver Lung Renal
Ethanol 0.5 2 to 6 - 95 2 3 Methanol 0.6 to 0.7 14 to 30 43 to 96 97 2.5 1 Ethylene glycol 0.5 to 0.8 3 to 8 17 to 18 80 - 20 Diethylene glycol 1 4 to 6 ? 30 to 50 - 50 to 70 Propylene glycol 0.5 1.4 to 3.3 17 55 to 75 - 25 to 45 Isopropanol 0.5 2.5 to 6.4 ? 80 -90 - 10 to 20 _______________________________________________________________________
TOXICOKINETICS OF DEG – METABOLISM
Limited data in human
T1/2 ~ 3.6 hr in rats
Does not appear to be metabolised to EG
Patient poisoned by DEG showed no Ca oxalate crystals in the urine
TOXICOKINETICS OF DEG – ELIMINATION
Renal excretion of DEG and its metabolites is the predominant route
In rats, 61-68% is excreted via kidney unchanged, 16-31% is excreted as HEAA (2- hydroxyethoxyacetic acid)
MECHANISM OF TOXICITY DEG is direct toxic? HEAA is the major contributor to the renal and neurological toxidromes Membrane destabilization via phospholiod or ion channel effects, intracellular accumulation of osmotically active metabolites with associated transcellular fluid shifts HEAA HAGMA
Small dose acute toxicity with injury or delayed lethality, affect the kidneys, livers and delayed lethal neurological damage
Large dose CNS depressant, within 24 hrs
CLINICAL FEATURES Varies with amount of ingestion, coingestion of other alcohol
phase onset feature 1 Delayed up
to 48 hrs GI – N, V, abd pain, diarrhoea CNS – Drunk like CVS – mild hypotension Metabolic – +/- high OG, HAGMA
2 1-3 days Renal – oliguric, flank pain, ARF (convoluted tubules necrosis) Hepatic – raise ALT (centrilobular necrosis), amylase Dead is imminent in 2-7 days without RRT
3 10-14 days Delayed CNS cx – progressive lethargy, bil facial paralysis, dysphonia, dilated and nonreactive pupils, loss of gag reflex, loss of visual or auditory fx, tetraplegic, coma Peripheral neuropathy, inspiratory muscle weakness
DIAGNOSIS Dx by serum DEG level (GCMS)
High index of suspicion – Signal ! Cohort of patients, particularly children with ARF, MA, +/- pancreatitis, hepatitis, rapidly develop respiratory failure due to respi muscle weakness, coma, seizure, death High OG = measured osmo – calculated – ethanol (Lower OG was observed in DEG poisoning)
Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol 2008; 3:208–225.
EFFECT OF ALCOHOL / DRUGS ON SERUM OSMOLALITY
Substance Mole Wgt
mOsm/L* ΔSOsm (mOsm/L) per 10 mg/dl ΔSerum Alcohol concMethanol 32 34 3.09
Ethanol 46 23 2.12 Ethylene glycol 62 19 1.60 Acetone 58 18 18 Isopropanol 60 18 1.66 DEG 106 9 0.9 Salicylate 180 6 6
* At 100 mg/dl
OSMOL GAP: LIMITATIONS Normal Osmol Gap in setting of poisoning does not rule out a treatable level Osmol Gap diminishes as parent compound Useful prior to onset of acidosis or in massive overdoses Parent compound not directly toxic Levels not universally available
Time
Patients with acidosis should receive treatment
CONFIRMATORY TESTS Tests on toxic ingredient(s) of material Tests for biological specimens
Urine Blood, plasma, or serum
Qualitative vs Quantitative
GAS-CHROMATOGRAPHY INSTRUMENTATION
sufw 2010
3.50 4.00 4.50 5.00 5.50 6.00 6.50 7.00 7.50 8.00 8.50 9.00 9.50
200000
400000
600000
800000
1000000
1200000
1400000
1600000
1800000
2000000
2200000
2400000
2600000
Time-->
Abundance
SIMPLE QUALITATIVE TESTS?
Shin JM et al. Simple diagnostic tests to detect toxic alcohol intoxications. Transl Res 2008;152(4):194-201
LABORATORY TEST CBC, R/LFT/CaPO4/CPK alcohol toxicology panel with ethanol, isopropanolol and methanol determinations ABG ECG
DIETHYLENE GLYCOL POISONING: TREATMENT OBJECTIVES
Limit absorption:
Enhance elimination Parent Metabolites
IV access, Cardiac monitoring, Urinary catheter Fluids IV crystalloids 250-500ml/hr: increase renal clearance Treat seizure
2. Antidotes: Block mechanism Ethanol (competitive ADH substrate) Fomepizole (ADH inhibitor)
3. Haemodialysis: Remove agent Remove the toxic alcohol & its metabolites Correct acidosis ARF Shortens hospitalisation
4. NaHCO3 IVI Correct metabolic acidosis (pH<7.2) Increase renal excretion of toxic metabolite
Diethylene Glycol
Initial management:
• ABC’s (remember the impending CNS depression)
• Initiate specific treatment if ingestion strongly suggested – Do NOT wait for lab values
• Untreated, lethal dose (1ml/Kg) will cause death in about 24 hours.
MANAGEMENT – ANTIDOTE
Ethanol or fomepizole to reduce conversion to HEAA or other toxic metabolites
There is limited data on using fomepizole in DEG poisoning, but it is proven to be effective in EG poisoning
Diethylene Glycol
Goal of Specific Treatment:
1. Prevent further metabolism of toxic alcohol (by Inhibition of liver alcohol dehydrogenase )
2. Eliminate alcohol from circulation
Toxic Alcohol
INDICATIONS FOR ANTIDOTE TREATMENT
Definite history of ingestion( unknown dose) & osmolal gap >10mosm/L
Suspicion of intoxication plus at least 2 of: pH<7.3 HCO3 <20mmol/L Osmol gap >10
Diethylene Glycol
1. Ethanol Traditionally been used as antidote for Methanol and ethylene Glycol (never approved)
• Historical Case series/reports only (1st report: 1959) • Never prospectively/retrospectively studied
• Preferred substrate of alcohol dehydrogenase therefore inhibits formation of NEW toxic metabolite
Toxic Alcohol
• What amount will completely block the metabolism of methanol/ethylene glycol?
• Objective (regardless of route): quickly achieve and maintain ethanol level ≥ 22 mmol/L
Ethylene Glycol
• Can be given IV or PO. (oral absorption is erractic and not recommended)
Ethanol – How to give.
ETHANOL Target concentration 100 mg/dL
0.8 gm/kg loading IV of 10% solution in D5W over 1 hour = 8 mL/kg of 10% solution
Maintenance Dose 66-130 mg/kg/hr (Needs to be increased to 250 mg/kg/hour or
higher during dialysis )
ETHANOL Pro’s
Cheap and always available (oral/NG if not IV) More widely used than Fomepizole
Con’s Narrow therapeutic index Serial ethanol levels ( ICU/HDU case for hourly check ) Watch glucose* and sodium* Observe for respiratory status*, hypoglycemia, gastritis and pancreatitis Duration can take as long as 100 hrs (depending on dialysis)
Approved by FDA for E.G. poisoning in 1997, and for methanol poisoning in 2000
Fomepizole (4-methypyrazole)
Diethylene Glycol
1.Megarbane B, Borron SW, Trout H et al. treatment of acute methanol poisoning with fomepizole. Intensive Care Med. 2001. 27:1370-1378 2.Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of ethylene glycol poisoning. NEJM. 1999. 340:832-838 3.Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of methanol poisoning. NEJM. 2001. 344:424-429
Diethylene Glycol
• Competitive Inhibitor of Alcohol dehydrogenase • (in vitro: 80,000 times affinity for ADH than methanol)
Toxic Alcohol
• Competitive Inhibitor of Alcohol dehydrogenase • (in vitro: 80,000 times affinity for ADH than methanol)
Toxic Alcohol
HEAAHEAA
Can be given PO or IV
1. Loading Dose: 15 mg/kg (Dilute dose in 100 ml NS or D5W over 30 minutes)
2. Maintenance: 10 mg/kg bolus q12 h x 48 hrs 3. Maintenance: 15 mg/kg bolus q12 h until end 4. During hemodialysis, dose Q4H
Fomepizole – Advantages:
1. Does not require separate preparations 2. Wide Therapeutic index 3. No GCS change, hypoglycemia, hepatotoxicity 4. Few side effects (headache , nausea, dizziness)1,2
5. Evidence of successful treatment without HD/HF
Main Disadvantage: Cost! Apr. $1000 US per 1500 mg vial Suggested shelf life of drug ~ 3 yrs No prospective study comparing against ethanol Not widely available 1. Megarbane B. Current recommendations for treatment of severe toxic alcohol poisonings . Intensive Care Medicine  2005; 31:189195 2. Brent J. Fomepizole for the treatment of ethylene glycol poisoning. New England Journal of Medicine 1999; 340:832838 3. Borron SW. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. The Lancet 1999; 354:831
Diethylene Glycol
Dose fomepizole obviate the need for HD?
Fomepizole pharmacokinetics in children?
Fomepizole regimen in children
MANAGEMENT – ENHANCED ELIMINATION
HD and Haemodiafiltration have been used successfully to treat both EG and methanol toxicity, but limited information about its use in DEG intoxication But DEG is of low molecular wt, not protein bound good candidate But it is not certain HEAA is dialysable
Removes Diethylene Glycol and metabolites Treats metabolic acidosis Supports acute kidney injury Reduces necessary duration of antidotal treatment Hemodialysis indicated if:
The triad of history, clinical presentation, and lab results consistent with DEG poisoning are present Signs of nephrotoxicity (DEG) or CNS disturbances Severe metabolic acidosis
ADJUNCTS FOR DIETHYLENE GLYCOL POISONING
To enhance metabolism*
Pyridoxine 50 mg every 4-6 hours
* Limited data
Early suspicion & treatment Delays lead to Renal failure
Death
PROGNOSIS AND OUTCOME Reported high mortality rates up to 90% were due to late presentation of unsuspected case Usually were dialysis-dependent in those who survived from DEG poisoning
Developing countries are at higher risk for medication- associated DEG mass poisoning because of less effective quality control procedure by persons or businesses that handle substances intended for incorporation into pharmaceutical products
SUMMARY For DEG Poisoning
Caution in using osmol gap
Antidote: Ethanol or Fomepizole
THE CONTINUED OCCURRENCE OF MEDICATION-ASSOCIATED DEG MASS POISONING
1. Intent to deceive persons and organizations within the pharmaceutical manufacturing process, including brokers and traders, as to an ingredient’s true identity, probably for financial gain
2. A lack of adherence to universal GMP and adequate quality control standards, thereby leaving vulnerabilities
Schier JG et al Medication-associated diethylene glycol mass poisoning. A review and discussion on the origin of contamination. J Public Health Policy 2009; 30:127-143
GUIDANCE FOR INDUSTRY TESTING OF GLYCERIN FOR DEG
US Department of Health and Human Food and Drug Administration
Center for Drug Evaluation and Research May 2007
REFERENCE 1. Schep LJ et al Review: Diethylene glycol poisoning. Clinical Toxicology 2009;
47:525-535 2. Schier JG et al Medication-associated diethylene glycol mass poisoning. A
review and discussion on the origin of contamination. J Public Health Policy 2009; 30:127-143
3. Kraut JA. Toxic Alcohol Ingestions: Clinical Features, Diagnosis, and Management. Clin J Am Soc Nephrol 2008;3:208-225
4. Megarbane B, Borron S.W, Baud F.J. Current recommendations for treatment of severe toxic alcohol poisonings.Intensive Care Med (2005) 31:189-195
5. Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of ethylene glycol poisoning. NEJM (1999) 340; (11):832-838
6. Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of methanol poisoning. NEJM (2001); 344:424-429
7. Brindley P.G, Butler M.S, Cembrowski G, Brindley D.N. Falsely elevated point of care lactate measurement after ingestion of ethylene glycol. Canadian Medical Association Journal (2007) 176;(8):1097-1099
THANKS FOR YOUR ATTENTION