ToxCard: PNU (Vacor)

Authors: Rosa Malloy Post (@postponemyloanz, Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center); Christine Murphy, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: Christopher Counts, MD (Medical Toxicology Fellow, Rutgers New Jersey Medical School, Newark, NJ); Cynthia Santos, MD (Emergency Medicine Attending, Medical Toxicologist, Rutgers New Jersey Medical School); James Dazhe Cao, MD (@JamesCaoMD, Associate Professor of EM, Medical Toxicology, UT Southwestern Medical Center, Dallas, TX); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 3-year-old otherwise healthy male presented to the emergency department (ED) with altered mental status, intractable vomiting, and hyperglycemia. The father reported the patient was in his usual state of health approximately two hours ago. He has been with his father cleaning the basement of his recently deceased grandfather’s home, when he was found among  canisters and old boxes of household supplies. He had a cornmeal-like substance around his mouth and covering his shirt. Shortly after this, he began vomiting, and developed a tonic clonic seizure. On arrival to the ED, the patient was agitated, disoriented, tachycardic, and his blood glucose was > 600 mg/dL. There was no prodromal illness, recent trauma, polyuria or polydipsia, family history of seizure disorder or diabetes. Physical exam was significant for horizontal nystagmus with bilateral lower extremity hyporeflexia and profound orthostatic hypotension. Laboratory studies were significant for hyperglycemia, elevated anion gap metabolic acidosis, and ketonuria.

Questions

1. What is PNU?
2. When should I suspect PNU poisoning?
3. How do I treat PNU poisoning?

Background:

• N-3-pyridylmethyl-N-p-nitrophenylurea (PNU, Pyrinuron, Pyriminil) was released in 1975 as a “safe” poison to use against mice resistant to anticoagulant rodenticides.¹
• PNU was sold under the trade names Vacor, Rat Killer, DLP-787 20% bait, and DLP-787 10% house mouse tracking powder.¹
• PNU is reported to have a cornmeal-like appearance and peanut butter scent.¹
  • Unfortunately, packages of Vacor were also similar in appearance to those of instant oatmeal at the time, and multiple fatalities occurred after exploratory ingestions by toddlers.²
• PNU was withdrawn from the US market in 1979, however, there is still active small-scale manufacturing in the People’s Republic of China, and it is available online for purchase as a research chemical.¹
• The toxic doses in humans have ranged from 0.39 to 7.0 grams.³
  • More severe CNS symptoms were recorded at doses higher than 2 grams.

Mechanism of Action: 

• PNU interferes with nicotinamide adenine dinucleotide (NAD) production by acting as a nicotinamide agonist.⁴
• It is metabolized by the enzymes nicotinamide phosphoribosyl transferase (NAMPT) and nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) consecutively into a NAD analog called vacor adenine dinucleotide (VAD).⁴
• VAD interferes with NAD-dependent reactions of glycolysis and triggers cell death of NMNAT2-expressing cells, which are primarily pancreatic beta islet cells and neurons.⁵
• This leads to the destruction of the pancreatic beta cells and patients can no longer secrete insulin. In essence, it induces Type 1 diabetes.⁴
• PNU is such a potent beta islet cell poison, it is used by molecular biologists to induce type 1 diabetes in mice and is being studied as a chemotherapy agent in neuroblastoma and melanoma.⁴

Clinical Presentation: 

• Initial presentation can be characterized by vomiting, severe diabetic ketoacidosis, and autonomic instability.
• Diabetic ketoacidosis (DKA) is the most common presentation following acute exposure.
  • In case reports, the onset of DKA has ranged from hours to days from time of ingestion.⁵
  • There may be a triphasic effect on blood glucose/the pancreas similar to that seen in streptozocin and alloxan toxicity.⁵ In animals given streptozocin and alloxan, there is an initial period of hyperglycemia, followed by a period of severe hypoglycemia and then the development of chronic/permanent hyperglycemia.⁵
• Autonomic instability most notably presents in the form of orthostatic hypotension that can persist long-term.³
  • Autonomic instability can worsen over the first few days, even if treated early with nicotinamide to the point of areflexia, anhidrosis, urinary retention, dysphagia, and ptosis.3
• Other symptoms can include hypomotility of the GI tract, peripheral neuropathy, and encephalopathy.³
  • Peripheral neuropathy, both sensory and motor, can develop within the first few days.

Diagnosis: 

Although PNU has not been commercially available since 1979, it is reasonable to consider PNU-related toxicity in cases of sudden onset DKA without precipitating factors, coupled with acute autonomic instability and history concerning for possible ingestion. Symptoms generally occur within hours of exposure. In these cases, PNU ingestion would most likely originate from exposure to an old household rodenticide or exposure to a “research chemical”.

• Testing:
  • There are no commercially available tests for PNU.
  • Lab results would be expected to show hyperglycemia, ketonuria, elevated anion gap metabolic acidosis, and an elevated beta-hydroxybutyrate. Obtain the following:
    • Electrolytes
    • Urinalysis
    • Beta-hydroxybutyrate
    • Venous/arterial blood gas
    • Acetaminophen and salicylate levels if there is a history of intentional ingestion

• Neurology consultation is warranted in the setting of DKA with associated weakness, neuropathy, or autonomic symptoms. 

Management: 

• Consider consulting a regional poison control center (in the US can call 1-800-222-1222) or local medical toxicologist to discuss the diagnosis and management following PNU exposure. 
• Activated charcoal can be used to prevent absorption in acute ingestions, presenting within an hour of exposure.³
• When administered early after overdose, nicotinamide may decrease the severity of toxicity. Empiric treatment is recommended given low toxicity of nicotinamide.³ 
  • Nicotinamide has a higher affinity for NMNAT than PNU.  
  • Suggested dosing from one case series is 500 mg IV via slow push followed by 100 to 200 mg IV every four hours for 48 hours.  
  • Niacin has been used but has a lower bioavailability than nicotinamide and can cause hypotension when given.³
  • Nicotinamide is not widely available, so you may need to consult with your pharmacist or local medical toxicologist.

• Treat the DKA as you would with any other patient; insulin, appropriate fluid resuscitation, and electrolyte repletion.  
• Orthostatic hypotension can persist for months after ingestion. There is limited data describing the treatment of this. In one case, dihydroergotamine worked better than fludrocortisone.⁶

Clinical Pearls:  

• PNU leads to beta islet cell destruction and induces permanent type 1 diabetes. 
• Treatment is the same as for a patient with DKA from new-onset diabetes. 
• Fortunately, PNU poisoning is rare. However, consider PNU poisoning in a patient with new autonomic instability, DKA, and possible exposure to the chemical.

Case Follow-up:

The patient was admitted to the pediatric intensive care unit. He was treated for diabetic ketoacidosis with improvement of his blood sugars and resolution of his anion gap. His neurologic symptoms resolved fully by hospital day 2. Unfortunately, he developed persistent hyperglycemia and was diagnosed with insulin dependent diabetes. As no definitive testing could be performed on the material ingested, it could not be confirmed whether the patient’s symptoms were related to a PNU exposure or new onset diabetes, however, PNU exposure was highly suspected.

References:

1. Pelfrène AF. Rodenticides. In: Krieger R, ed. Hayes’ Handbook of Pesticide Toxicology. Elsevier; 2010:2153-2217. doi:10.1016/b978-0-12-374367-1.00100-2
2. Schum TR, Lachman BS. Effect of Packaging and Appearance on Childhood Poisoning. Clinical Pediatrics. 1982;21(5):282-285. doi:10.1177/000992288202100504
3. LeWitt PA. The neurotoxicity of the rat poison vacor. A clinical study of 12 cases. N Engl J Med. 1980;302(2):73-77. doi:10.1056/NEJM198001103020202
4. Buonvicino D, Mazzola F, Zamporlini F, et al. Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites. Cell Chem Biol. 2018;25(4):471-482.e7. doi:10.1016/j.chembiol.2018.01.012
5. Johnson D, Kubic P, Levitt C. Accidental Ingestion of Vacor Rodenticide: The Symptoms and Sequelae in a 25-Month-Old Child. Am J Dis Child. 02 1980;134(2):161-164. doi:10.1001/archpedi.1980.02130140035012
6. Benowitz NL. Dihydroergotamine Treatment for Orthostatic Hypotension from Vacor Rodenticide. Annals of Internal Medicine. 1980;92(3):387. doi:10.7326/0003-4819-92-3-387