Results tagged “toxicology” from Pathophilia

From Pediatrics: a study of tobacco poisonings in young American children.

• From 2006 to 2008, 13,705 cases of tobacco poisoning were reported.
• About 70% of cases occurred in kids younger than 1 year of age.
• Nearly 80% of poisonings were due to the ingestion of cigarettes and (or?) filter tips (vs smokeless tobacco or cigars).

Plus there's commentary on a charming, new Tic Tac-like product from RJ Reynolds: cinnamon- or mint-flavored Camel Orbs, which contain 1 mg of nicotine per pellet. Although the product is new to the market, there has been at least 1 reported case of tobacco poisoning due to the ingestion of Camel Orbs (by a 3-year-old child).

RJ Reynolds also markets flavored Camel Sticks and Camel Strips.

Last year, the FDA was given the authority to regulate flavored cigarettes (but not other flavored tobacco products), thanks to the Family Smoking Prevention and Tobacco Control Act. The agency was quick to ban candy-, fruit-, and clove-flavored smokes in the United States.

Image of Camel Orbs from dissolvables.tobaccopleasure.com.

Unexplained bone-marrow failure (ie, agranulocytosis) in residents of New Mexico, Washington, and Canada led to the discovery of levamisole, an antiparasitic antibiotic, as a prevalent cutting agent in cocaine. A report of the investigation by public health officials, which began last year and identified 21 affected Americans, is available in the latest issue of MMWR.

According to the report, levamisole, as a treatment for rheumatoid arthritis or breast cancer, causes agranulocytosis in 2.5%-13% of patients; however, use of the drug is currently and primarily restricted to veterinary practice (eg, to deworm livestock and aquarium fish).

As of July of this year, about 70% of seized cocaine entering the United States contained levamisole, according to the DEA. The concentration of the additive is approximately 10%, says the agency. Given these statistics, MMWR editors suspect that levamisole-associated agranulocytosis due to cocaine use is vastly underrecognized and underreported.

The reason why levamisole, in particular (versus, say, Italian baby laxative a la Atlantic City) is added to cocaine "remains unclear." Online sources indicate that the antibiotic is a white- to pale cream-colored, odorless or nearly odorless, crystalline powder.

According to the SF Chronicle, by way of Wikipedia, levamisole and cocaine were detected in the body of DJ AM.

A new report may put the kibosh on Halloween face painting.

Minuscule, but measurable, amounts of lead were found in all samples of commercially available brands of face paint that were sent for testing by the nonprofit The Campaign for Safe Cosmetics (TCSC). In addition, 6 of the brands contained levels of heavy-metal allergens (nickel, cobalt, or chromium) that exceeded recommended standards for consumer products (1 ppm).

Ten face paints—many of which were marketed for children—were purchased through Amazon.com and sent for heavy-metal testing at an independent laboratory, Analytical Sciences in Petaluma, California. Four of the brands were manufactured in China. Other countries of origin were the United States (4), the United Kingdom (1), and Spain (1).

Paint Brand	Manufacturer	Location	Heavy Metal Content, ppm
			Pb	Ni		Co		Cr
Alex Face Paint Studio	Alex Toys	China	0.650	—		—		—
Don Post Grease Paint Color Wheel	Don Post Studios	China	0.630	—		—		15
Snazaroo Face Painting Kit	Snazaroo	UK	0.560	5.5		5.5		—
Rubie’s Silver Metallic Fard d‘Argent	Rubie’s Costume Co	USA	0.260	2.1		—		2.2
Ben Nye Lumiere Wheel	Ben Nye Co, Inc	USA	0.190	—		—		—
Wolfe Face Art & FX	Wolfe Face Art & FX	China	0.180	—		—		1.6
Mehron Glow in the Dark Fantasy F-X	Mehron Inc	USA	0.140	—		—		—
Crafty Dab Face Paints Push-Up Crayons	Crafty Dab	China	0.082	—		—		—
Mehron 6-Pack Greasepaint Crayons	Mehron Inc	USA	0.074	4.1		4.8		16
Jovi Make-up	Jovi	Spain	0.054	5.9		—		120
Recommended limit			0		≤1	≤1	≤1

Detectable levels of mercury or arsenic were not found.

The study was prompted by the discovery of lead in top-selling lipsticks in 2007* and reports of heavy metals in kids' face paints sold in other countries (eg, here, here, and here).

TCSC states that there is currently no way to determine if a particular brand of cosmetic contains heavy metals unless testing is conducted by the consumer herself. The organization charges that the FDA "does little to ensure that cosmetics are safe and actually lacks the power to do so...the FDA does not conduct routine testing of cosmetic products and does not have the authority to require companies to conduct pre-market safety assessments of their products or the ingredients in them. The FDA also does not require companies to list heavy metals or other harmful contaminants on product labels, even though they are commonly found in a wide array of personal care products." 

The cost of testing each brand of face paint for heavy metals was $270 per sample.

Whether small amounts of lead in the infrequently used face paint should be a concern is debated; however, there is no good reason for heavy metals to exist in cosmetics or similar products intended for children.

Last winter, contaminated face paint caused skin reactions, some photosensitive, in participants at a Girl Scout event. The paint was manufactured in China.

ppm = parts per million.

* Last month, the FDA reported lead levels in lipstick that were higher than those discovered in 2007 by The Campaign for Safe Cosmetics.

Image of Alex Face Paint Studio, which contained the highest level of lead among the paint brands sampled, from Amazon.com.

A newly released affidavit reveals the last hours of Michael Jackson's life, as told to an LAPD homocide detective by Jackson's personal physician, Conrad Murray. The affidavit, which was used to support a search warrant of Conrad's storage locker in Houston, Texas, also reveals the preliminary and not-so-surprising cause of Jackson's death: a lethal dose of propofol, aka Diprivan. Contrary to popular speculation (and common sense), Jackson did not receive the anesthetic until the mid-morning hours on the day of his death, June 25th (at least that's what the doctor reportedly claimed).

Here's what allegedly went down on that day at Jackson's rented home in Los Angeles:

@ 01:30—Murray gives Jackson a 10-mg tablet of diazepam (Valium) for insomnia. Jackson is unable to sleep.

@ 02:00—Murray gives Jackson lorazepam (Ativan) 2 mg by slow IV push. Jackson is unable to sleep.

@ 03:00—Murray gives Jackson midazolam (Versed) 2 mg by slow IV push. Jackson is unable to sleep.

@ 05:00—Murray gives Jackson another 2-mg dose of lorazepam by slow IV push. Jackson remains awake.

@ 07:30—Murray gives Jackson another 2-mg dose of midazolam by slow IV push. Jackson remains awake.

@ 10:40—After repeated demands by Jackson, Murray administers propofol 25 mg IV after lidocaine pretreatment.

@ 10:50—Murray leaves Jackson's bedside to go to the restroom.

@ 10:52—Murray returns to find that Jackson is not breathing. (Murray stated to investigators that Jackson had been continuously monitored throughout this time with pulse oximetry.) Murray begins CPR (presumably while Jackson remains on the bed) and administers 0.2 mg of flumazenil (Anexate), a benzodiazepine antagonist. Using his cell phone, Murray also calls Jackson's personal assistant and requests that security personnel be sent upstairs for an emergency.

A few minutes later, Murray runs downstairs to the kitchen and (inexplicably) asks the chef to send up Jackson's oldest son. Murray returns to Jackson to continue CPR. Jackson's son responds and summons security detail.

11:18-12:05—Phone records reveal that Murray was on his cell phone for approximately 47 minutes with 3 separate callers; although Murray did not reveal these calls to investigators at the time of the interview.

@ 12:21—Michael Jackson's bodyguard, Alberto Alvarez, goes to Murray and calls 911 on his cell phone.

@ 12:22—An LA Fire Department ambulance responds to Jackson's home. Murray informs the paramedics that he is Jackson's personal physician and that he had continuously administered CPR, for respiratory arrest, until their arrival. Murray also divulges that he had given Jackson lorazepam before his respiratory arrest.

While continuing resuscitation efforts, the paramedics transport Jackson and Murray to the UCLA Medical Center.

@ 14:26—After a protracted effort to revive Jackson at UCLA, Jackson is pronounced dead. Murray allegedly did not reveal to emergency physicians that he had given Jackson propofol. He also refused to sign Jackson's death certificate.

Early in the course of their death investigation, the LAPD evidently could not locate Murray. At Jackson's home, "numerous" bottles of medications were found, which had been prescribed by Murray for Jackson—including the benzodiazepines diazepam, lorazepam, and temazepam (Restoril). Bottles of clonazepam (Klonopin) and the antidepressant trazodone (Desyrel) were also found, which had been prescribed by internist Allan Metzger. And a bottle of the muscle relaxant tizanidine (Zanaflex) had been prescribed to Jackson by his dermatologist, Arnold Klein.

Four days later, investigators, armed with a search warrant, discovered vials of lidocaine, propofol, lorazepam, midazolam, and flumazenil at Jackson's home. None of these medications were associated with an identifiable prescription. The affidavit also reveals that the Drug Enforcement Agency (DEA) could not find a record of Murray purchasing, ordering, or obtaining propofol with his medical license number or DEA number.

Murray admitted that he had been treating Jackson's insomnia with propofol 50 mg IV every night for the last 6 weeks. According to the affidavit, he had successfully reduced the propofol dose to 25 mg on June 22nd, while also administering lorazepam and midazolam to Jackson. The following night, Murray claimed that he was able to induce sleep with only lorazepam and midazolam.

Not sure which is more shocking: The report that at least 20 non-OTC drugs were recovered from Michael Jackson's home or the fact that ABC News is sourcing The Sun on this one. Maybe ABC's reporters were impressed by alleged autopsy information printed last week by the tabloid—namely that Jackson's arms were riddled with needle marks. Yesterday ABC reported the same ("Jackson's arms were scarred with track marks"), citing "investigators."

On the basis of reportage from ABC and The Sun, the partial, cobbled-together list of drugs (save propofol [Diprivan]) found in Jackson's home includes the following (in alphabetical order):

1. Demerol: Generic names, meperidine and pethidine. A fast-acting opioid available in injectable and oral formulations. Legitimate use has become unpopular during the last 2 decades, owing to the drug's potential neurotoxicity and abuse potential. Jackson allegedly took Demerol daily and possibly several times a day.
2. Dilaudid: Generic name, hydromorphone. A morphine derivative available in injectable and oral formulations. Typically used for pain management.
3. Fentanyl: A highly potent synthetic opioid available in injectable, transdermal patch, and "lollipop" formulations. Typically used in anesthesia induction and pain management.
4. Lidocaine: Presumably in the form of low-concentration vials to produce local anesthesia. Possibly used in conjunction with propofol to reduce injection-associated pain.
5. Methadone: A synthetic oral opioid. Most commonly used as a maintenance medication when kicking opioid addiction.
6. OxyContin: Generic name, oxycodone. A wildly popular, semi-synthetic oral opioid. Jackson allegedly took the medication daily.
7. Paxil: Generic name, paroxetine. An orally administered, selective serotonin-reuptake inhibitor (SSRI). Indicated for the treatment of depression, OCD, panic disorder, anxiety disorders, and PTSD.
8. Percocet: Generic ingredients, oxycodone (same as OxyContin) and acetaminophen (eg, Tylenol). Typically prescribed short term for pain relief.
9. Soma: Generic name, carisoprodol (a metabolite of meprobamate, aka Miltown). An orally administered, centrally acting muscle relaxant that potentiates opioid-induced analgesia.
10. Versed: Generic name, midazolam. A very-short-acting benzodiazepine in oral and injectable formulations. Typically used as a premedication before surgical or medical procedures.
11. Vicodin: Generic ingredients, hydrocodone and acetaminophen. Orally administered and should be prescribed short term for pain relief. (N.B.—I've witnessed physicians dispense this drug like Pez candy.)
12. Xanax: Generic name, alprazolam. An orally administered, short-acting benzodiazepine. Prescribed for anxiety and/or sedation.
13. Zoloft: Generic name, sertraline. An orally administered SSRI. Indicated for the treatment of depression, OCD, panic disorder, anxiety disorder, PTSD, and premenstrual dysphoric disorder (which Jackson presumably did not have).

There are a number of permutations for lethal combinations of these drugs, some of which can kill all by themselves. Perhaps more surprising than Jackson's death is his survival—given the duration of his alleged polypharmacy use and dependence.

OCD = obsessive-compulsive disorder; OTC = over the counter; PTSD = posttraumatic stress disorder.

Props must be given to TMZ. Multiple news sources have been citing the entertainment news-gossip web site in the widespread coverage of Michael Jackson's suspect death.

The latest: Edward Chernoff, criminal defense lawyer for Conrad Murray (Michael Jackson's doctor), won't confirm or deny that Murray gave Jackson propofol (trade name, Diprivan). In a phone interview last night, Chernoff reportedly told TMZ, "I have no statement on whether the Dr. prescribed or administered Propofol." Although the lawyer was apparently willing to repeat that Murray did not administer Demerol or OxyContin to Jackson.

In its update, TMZ implies that Chernoff is now backtracking somewhat on last night's statements and "can't speak for anything that was in the [Jackson] home."

Image of Diprivan formulations from APP.

Sources are now implicating propofol (Diprivan; sanofi-aventis) in Michael Jackson's death. TMZ reports that police recovered the anesthesia inducer at Jackson's rented home. And ABC News interviewed Jackson's nutritionist, Cherilyn Lee, who stated that the singer asked her for Diprivan, by trade name, 3 months ago. Jackson's alleged intention, bizarre as it may sound, was to be put to sleep at home under the guidance of an anesthesiologist.

In use for more than 2 decades, Diprivan is a rapidly acting (within 40 seconds) IV sedative-hypnotic that is FDA approved for the induction and maintenance of anesthesia and for sedation in an intensive care unit (in both cases, patients are mechanically ventilated). According to the prescribing information, the induction dosage for ICU sedation begins at 5 microg/kg/min and should be titrated (by increments of 5-10 microg/kg/min) to the desired clinical effect. Maintenance rates are generally 5-50 microg/kg/min or higher for adults.*

For anesthesia induction, the typical dosage is 40 mg every 10 seconds in healthy adults younger than 55 years of age; maintenance of anesthesia can be achieved by intermittent boluses of 20-50 mg. However, slow infusion or injection techniques are recommended to avoid apnea and hypotension. Diprivan dosages should be reduced in patients who have received large doses of narcotics.

Common adverse events with Diprivan use include bradycardia or other arrhythmias, hypotension, and apnea. Burning pain or stinging at the injection site, which is also common, may be reduced by preinjecting the vein with a 1% lidocaine solution (1 mL).

Subanesthetic doses of Diprivan may have the potential for abuse by inducing euphoria. Diprivan's abuse potential is particularly high among physicians who have access to the drug—namely, anesthesiologists. An e-mail survey in 2007 indicated that Diprivan abuse has increased substantially in academic anesthesia departments during the last 10 years. Among the 25 reported abusers in the survey, 16 (64%) were resident physicians. Seven (28%) abusers died; 6 of the deceased were resident physicians. In academic centers where abuse occurred, none had established pharmacy protocols to account for the drug (as is done routinely with opiate medications).

In 2008, an anesthesia nurse was convicted of killing a University of Florida student, with whom he was infatuated, by injecting her with propofol in her home. The victim's propofol blood level was 4.3 microg/mL. The expected propofol concentration after a bolus induction dose of 2.5 mg/kg (175 mg for a 70-kg man) is 1.3-6.8 microg/mL.

If a vial or vials of Diprivan were indeed recovered from Jackson's home, it seems almost certain that the medication was palmed by someone who had access, rather than formally prescribed.

Addendum: It also appears that Diprivan can be purchased through online pharmacies. For instance, drugdelivery.ca offers a 50-mL prefilled syringe for $122.99 USD. The completion of a patient questionnaire is necessary (along with payment); it is not clear that a valid prescription is required.

* So for a 70-kg man (~154 lbs), 0.35 mg/min would be administered for induction, and the maintenance dosage ranges from 0.35 to 3.5 mg/min. Vials of Diprivan contain 10 mg/mL and come in 20-, 50-, and 100-mL vials.

Image of Diprivan formulations from APP.

07/04/09 update: Yesterday the AP, citing an anonymous law enforcement official, confirmed that Diprivan was found in Jackson's rented home. CNN also reported that Neil Ratner, an anesthesiologist, traveled with Jackson during his HIStory tour in the mid-90s. Ratner's NY medical license was suspended in 2002 after being convicted of insurance fraud.

Neurologic symptoms caused by occupational exposure to the solvent 1-bromopropane (ie, bromism) are anticipated to rise. This warning, presented in the latest issue of the MMWR, is in response to 2 recent case reports and an expected increase in the use of 1-BP as a substitute for ozone-depleting compounds (eg, chlorofluorocarbons), particularly in the electronics and dry-cleaning industries.

In one case, a 50-year-old man, who worked directly with 1-BP at an electronics plant, developed persistent cognitive dysfunction and a sensory neuropathy. Medical evaluation revealed a significantly low anion gap and an elevated serum bromide level, characteristic of bromide toxicity. OSHA-sampled air at his workplace, where he did not use personal protective equipment (PPE), was considerably elevated above that recommended by professional organizations.*

The second case was a 43-year-old dry cleaner who experienced a number of neurologic symptoms, including headache, visual problems, paresthesias, and muscular twitching, after working with 1-BP (DrySolv) without PPE. The air in his work environment also revealed high levels of 1-BP.

The MMWR advises that physicians should remain vigilant for the possibility of 1-BP toxicity, especially in employees of dry-cleaning businesses (estimated at 110,000 Americans) as they transition from the use of the solvent perchloroethylene to the more environmentally friendly 1-BP. In some states—eg, California and New Jersey—this transition has been mandated by legislation. The substitution of 1-BP for perchloroethylene at dry-cleaning operations requires substantial modifications to equipment, such as the upgrading of vapor-control systems, which small businesses may not readily accommodate.

Historically bromism was seen in individuals who consumed the old sedative bromides chronically or in large amounts. More recently bromide toxicity could be seen after exposure to methyl bromide gas, a fumigant insecticide and an ozone-depleting compound that is also being phased out. Acute intoxication causes malaise, nausea, vomiting, followed by visual disturbances, mental dysfunction, ataxia, tremor, myoclonus, and seizures. Chronic exposure can cause neuropathy, cerebellar dysfunction, and symmetric brain lesions on MRI.

The mechanisms by which bromide causes neurologic dysfunction are unknown; however, it is speculated that clinical bromide toxicity may be manifestation of an "energy deprivation syndrome," in which metabolic pathways are disrupted—an explanation that's about as satisfying as diagnosing "toxic-metabolic encephalopathy" (ICD-9-CM 348.31).

OSHA = Occupational Safety and Health Administration. 

* OSHA does not presently have a permissible exposure limit for 1-BP.

David's rendering of polluting dry cleaners from the National Institute of Environmental Health Sciences.

In a welcome study of poorly regulated dietary supplements, investigators in Boston report the presence of toxic heavy metals—namely lead, mercury, or arsenic—in one fifth of US- or Indian-made Ayurvedic products. Results of a metal survey of these Internet-sold drugs were published in the latest issue of JAMA.

Among 199 of 230 randomly selected Ayurvedic medicines available for web-based purchase,* nearly 21% contained metals per x-ray fluorescence spectroscopy, wrote the authors, with no appreciable difference between US- and Indian-made products. Rasa shastra drugs—which combine herbs with metals, minerals, and gems—were significantly more likely to contain metals than non-rasa shastra products (41% vs 17%) and contained significantly higher median concentrations of lead (11.5 vs 7.9 µg/g) or mercury (20,800 vs 34.5 µg/g).

The amount of metals detected in metal-containing products consistently exceeded one or more standards for acceptable daily intake. These drugs were much more likely to be sold at US web sites (Table), and 75% claimed Good Manufacturing Practices, wrote the authors. In some cases, products were specifically recommended for pediatric use.

Product(s)	Manufacturer	US Web Site	Metal(s) Detected†
Prana-Breath of Life	Ayurherbal Corporation	By the Planet	Lead and/or mercury
AyurRelief, GlucoRite	Balance Ayurvedic Products	Balance Ayurvedic Products	Lead
Mahasudarshan	Banyan Botanicals	The Ayurvedic Institute	Lead
Kanchanar Guggulu, Shilajit	Banyan Botanicals	Banyan Botanicals	Lead
Acnenil, Bakuchi, Brahmi, Chairata, Cold Aid, Trifala Guggulu, Heart Plus, Jatamonsi, Kanta Kari, Licorice, Praval Pisti, Prostate Rejuv, Sugar Fight, Tagar, Yograj Guggulu	Bazaar of India	By the Planet	Lead, mercury, and/or arsenic
Energize	Bazaar of India	Bazaar of India	Lead
Hingwastika	Bazaar of India	Herbal Remedies	Mercury
Lean Plus, Neem Plus	Tattva's Herbs	Tattva's Herbs	Lead

These findings are consistent with those of a previous report, in which 20% of 70 Ayurvedic products made in South Asia and sold in Boston contained higher-than-regulatory amounts of lead, mercury, or arsenic. Scores of clinically symptomatic cases of heavy-metal intoxication due to the ingestion of Ayurvedic drugs have been reported since 1978.

* One web-based supplier of Ayurvedic products refused to fill an order for 14 products after recognizing that the purchasers were authors of a previous study.

† Measurement greater than reporting levels for x-ray fluorescence spectroscopy (ie, lead, ≥5 microg/g; mercury, ≥20 microg/g; arsenic, ≥10 microg/g).

A cautionary note to gray panthers: take it easy on the denture cream. Zinc in the grippy goo may lead to copper deficiency and associated neurologic illness.*

In this week's Neurology, physicians from the University of Texas Southwestern Medical Center report 4 patients with neurologic abnormalities in the setting of copper deficiency (hypocupremia) and high zinc levels (hyperzincemia). All presented with clinical myeloneuropathy, and all demonstrated low levels of serum copper and high levels of serum zinc. 

Neurologic symptoms followed the excessive use of denture cream, 2 or more tubes per week for several years. In samples of Fixodent (P&G) or PolyGrip (GSK) denture cream, the authors found zinc levels that ranged from 17 to 34 mg/g and identified no other plausible source of zinc or reason for copper deficiency.

Moreover, in the 3 patients who discontinued the use of denture cream, serum zinc levels dropped. Copper supplementation normalized copper levels in all 4 patients and was associated with mild clinical improvement in 2 patients.

The neurologic conditions in these patients are believed to be due to zinc-induced copper deficiency. Excess zinc—either unintentionally or intentionally swallowed by the denture-cream user—acts as a functional copper chelator, by upregulating the production of copper-binding metallothionein. (The metallothionein-copper complex is excreted in the feces, thereby causing copper deficiency.)

Removal of zinc from denture creams may be problematic, because the saliva-activated adhesive is generally a calcium-zinc polymer. Replies to e-mail inquiries sent to P&G and GSK, asking for comment on the Neurology case reports, are pending.

* Clinically similar to subacute combined degeneration associated with vitamin B12 deficiency.

Photo: iStockPhoto.

Addendum: In a formulaic-type e-mail, GSK, maker of Poligrip products, writes, "When someone uses Super Poligrip for their dentures, the vast majority of the zinc in the product remains in the adhesive and is not released into the mouth. Absorption through the gums, if any, is minimal. This is because the pH level of saliva [generally weakly acidic to neutral] in the mouth prevents the zinc from being released." GSK adds, "Swallowing small amounts of denture adhesive when used as directed is not harmful," and notes that there are Poligrip products that do not contain zinc.

9/11/08 addendum: At last, a response from P&G, or really "Fixodent," or really Ruth...

Thanks for contacting Fixodent, Barbara.

We appreciate your patience while we researched. Our products and their ingredients undergo rigorous scientific evaluations and safety testing before going to market. They are manufactured and packaged in accordance with FDA's good manufacturing practices. We meet all local laws and regulations where we sell Fixodent. We also continually monitor the safety of our products once in market.

Fixodent does not contain harmful ingredients and is safe when used as directed. Zinc is essential to good health. The amount of zinc an average denture adhesive user would ingest from daily usage of Fixodent is less than the amount of zinc in a daily multi-vitamin; less than 6 oysters (fried or raw); comparable to 6 oz. beef tenderloin.

I hope this information is helpful.

Ruth

P&G Team

Physicians in Leipzig, Germany, identified lead intoxication in 29 regular smokers of marijuana, according to correspondence in the latest issue of the NEJM. Elemental lead was discovered by means of atomic absorptiometry or plain-old eyeball (left) in partially used weed samples from 3 of the affected users. It is believed by authorities that the lead was deliberately cut into the marijuana to increase its weight and therefore the profits from a street product that is sold by the gram. The lead is thought to be easily absorbed through the respiratory tract, once the tainted marijuana is smoked.

Photo: Close-up of partially used dime (euro) bag of marijuana with visible, grayish lead particles from the NEJM.