Pharmocology/Pharmokinetics: Unclear overall

• Propylene glycol: absorbed by GI tract, Vd 0.6L/kg, may be absorbed percutaneously through damaged skin areas, 12-45% excreted unchanged in the urine, otherwise metabolized in the liver
• • WHO maximum allowable intake 25 mg/kg

Metabolic Pathways and Active Metabolites:

• Propylene glycol -> lactaldehyde->lactic acid by alcohol dehydrogenase
  • Then to pyruvate

Toxicity/Mechanism of Toxicity:

• Much more likely to be symptomatic from pod exposure vs regular detergent. Unclear  whether the significant adverse health effects observed with laundry detergent pod exposures relate to unique ingredients, differences in pH or other chemical properties.
• Ethoxylated alcohols may cause gastric irritation and lethargy
• Direct contact may cause irritation of the oropharynx and esophagus
• Aspiration and resulting pulmonary toxicity may occur with or without coincident CNS
  depression and vomiting

​​Propylene Glycol

• Cardiovascular: hypotension, bradycardia, widening of the QRS interval, increased T wave amplitude
• Neurotoxicity: Ethanol and/or PG may contribute to the CNS depression
  o Smaller infants have a decreased ability to clearPG
  o Case studies of seizures in lowbirthweight infants receiving 3g daily in parenteral multivitamins
• Hyperosmolarity, elevated osmolar gap, metabolic acidosis following metabolism
• Nephrotoxicity: rental tubular necrosis
• Is the dose of propylene glycol high enough in Tide Pods to cause significant long term
  damage? Unclear

Treatment:

• Topical exposure: Irrigation
• Ingestion: Supportive care, airway protection, IVF, oxygen 

​

Authored by Dr. Enola Okonkwo

 
Introduction
Artemether Lumefantrine is an oral medication which is used in treatment of chloroquine resistant uncomplicated malaria.  Artemether Lumefantrine falls within the drug class of Artemisinin-based combination therapies which have been found to be highly effective in treating malaria and are substantially less toxic than quinoline antimalarials.  Artemisins are derived from a Chinese medicinal herb which comes from the sweet wormwood plant (1).   Artemether Lumefantrine, known by the brand name Coartem, is the most widely used artemisinin based combination therapy used in Africa and is one of three medications recommended by the CDC as first line oral treatment for uncomplicated falciparum malaria within the United States (2). 

Structure

​1 tablet = 20mg artemether and 120 mg lumefantrine. 
Dosing is weight based.  For patients > 35 kg they are taking 4 tablets per dose twice daily for 3 days. 
 
Pharmacology/Pharmacokinetics:
Absorption/Distribution/Metabolism/Excretion
 
Artemeter is rapidly absorbed.  Peak plasma level of artemeter is approximately 2 hours. The half-life after ingestion is 2 hours (4-5). 95% of artemether is protein bound but quickly undergoes metabolism to dihydroartemisin which is approximately 50% protein bound.  Half life of dihydroartemisin is also around 2 hours (5). Bioavailability increased 2-3 fold when consumed with food (4).
 
Lumefantrine – Initial absorption at approximately 2 hours. Peak plasma level approximately 6-8 hours.    Half life is 4-5 days.  It is highly protein bound and has a large volume of distribution.  High fat meals significantly increase absorption 16 fold (4). 
   
 
Significant Drug/Drug interactions
Numerous theoretic drug interactions have been reported.  However, there is scant data available reporting clinical effects of drug interactions.
-May enhance QTc prolonging effects
-May enhance toxic effects of other antimalarial or HIV medications
-May increase serum concentration of antipsychotics
-May decrease serum concentration of estrogen related contraceptives
-May decrease serum concentration of CYP3A4 Substrates
 
Metabolic Pathways and active metabolites
 
Arthemeter is metabolized by the liver to the active metabolite dihydroartemisinin primarily by CYP3A4/5. 
 
Lumefantrine is metabolized by the liver to desbutyl-lumefantrine by CYP3A4. 
 
Studies suggest that artemisins inhibit the sarco/endoplasmic reticulum Ca ATPases of the malaria parasite causing rapid reduction in the parasite (6-7).  The mechanism of lumefantrine is unknown but both agents inhibit nucleic acid and protein synthesis.  Artemether rapidly kills the majority of the parasite and lumefantrine goes on to kill the residual remaining parasite (4-5). 
 
Mechanism of Toxicity
 
Artemether Lumefantrine has been extensively used for the treatment of malaria and appears to have an excellent safety profile.  There are no reported overdoses or intentional ingestions.  There has been no evidence of significant systemic or local toxicity reported in any large human study (1, 20-21).  However, there is animal data and a few small human studies and case reports which suggest neurotoxicity and QT prolongation are possible toxic effects of artimisinins (14). 
 
Neurotoxicity was especially common in animal studies both clinically and histologically (8-10, 14).  In vitro studies have postulated that neurotoxicity results secondary to ATP depletion of neurons and free radical generation created by the breakdown of artemisins (Schmuck 2002, Smith 1998) . Toover et. el wrote a review article cautioning that neurotoxic effects may also occur in humans more frequently than previously thought, though many critics viewed their review as bias (8, 13).  There are a small number of case reports within humans suggesting that artemisins contributed to neurologic symptoms such as anxiety, tremor, and ataxia (8, 15-16).  A small study looking at construction workers treated with arthemeter suggested that individuals had hearing loss following the administration of artemether (17).  Obviously, this study is limited by a serious potential confounder and attempts to reproduce these results have failed (18). 
 
One case report of delayed hemolytic anemia, not thought to be related to malaria was reported (19).
 
Clinical Toxicity
 
Given patients taking artemether lumefantrine have malaria, it is difficult to distinguish between symptoms caused by the disease state of malaria versus symptoms which may be attributed to medication toxicity.  Clinical toxicity appears to be very rare or possibly underreported.  A large review of 188 studies including over 9,000 patients found no serious clinical toxicity (21). This review article used methodology similar to Cochrane review and reported transient neutropenia in 1.3%, reticulocytopenia (0.6%), elevated liver enzymes (0.9%), and transient bradycardia and prolonged QT (1.1%).  The most common side effects reported were gastrointestinal.  The authors conclude that Artemether Lumefantrine is a safe and efficacious drug. 
 
Common adverse events (4, 20-21)
Abdominal pain
Anorexia
Vomiting
Diarrhea
Headache
dizziness.
Pruritis and Rash < 2%
 
Laboratories
No specific toxicology labs are available
 
Management of Toxicity
No accepted recommendations regarding toxicity given the scarcity of data suggesting toxicity.
Below are general recommendations based off of literature review:
Avoid concurrent use of additional antimalarial medications
Use caution administering additional drugs which can prolong QT
Use caution in hypokalemia and replete electrolytes as needed
Use caution in patients with prolonged QT
Obtain EKG as screening for arrhythmia
 
References:
 
1.  Hien, T. T., White, N. J., & White. (1993). Qinghaosu. The Lancet, 341(8845), 603–608. https://doi.org/10.1016/0140-6736(93)90362-K
 
2. Center for Disease Control. (2009). Guidelines for treatment of malaria in the United States. Treatment Table Update, May, (770), 855–857. Retrieved from http://scholar.google.com/scholar?hl=en&btnG=Search&q=intitle:Guidelines+for+Treatment+of+Malaria+in+the+United+States#1
 
3.  Amin, N. C., Fabre, H., Blanchin, M.-D., Montels, J., & Aké, M. (2013). Determination of artemether and lumefantrine in anti-malarial fixed-dose combination tablets by microemulsion electrokinetic chromatography with short-end injection procedure. Malaria Journal, 12, 202. https://doi.org/10.1186/1475-2875-12-202
 
4.  Waning, B., & Montange, M. (2015). Access Pharmacy. Retrieved from http://accesspharmacy.mhmedical.com/content.aspx?bookid=438&sectionid=40428529
 
5.  White, N. J., Van Vugt, M., & Ezzet, F. (1999). Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine. Clinical Pharmacokinetics. Adis International Ltd. https://doi.org/10.2165/00003088-199937020-00002
 
6.  Krishna, S., Pulcini, S., Moore, C. M., Teo, B. H. Y., & Staines, H. M. (2014, January). Pumped up: Reflections on PfATP6 as the target for artemisinins. Trends in Pharmacological Sciences. https://doi.org/10.1016/j.tips.2013.10.007
 
7.  Eckstein-Ludwig, U., Webb, R. J., Van Goethem, I. D. A., East, J. M., Lee, A. G., Kimura, M., … Krishna, S. (2003). Artemisinins target the SERCA of Plasmodium falciparum. Nature, 424(6951), 957–961. https://doi.org/10.1038/nature01813
 
8.  Toovey, S. (2006, October 10). Are currently deployed artemisinins neurotoxic? Toxicology Letters. https://doi.org/10.1016/j.toxlet.2006.06.001
 
9.  Genovese, R. F., Newman, D. B., Li, Q., Peggins, J. O., & Brewer, T. G. (1998). Dose-dependent brainstem neuropathology following repeated arteether administration in rats. Brain Research Bulletin, 45(2), 199–202. https://doi.org/10.1016/S0361-9230(97)00339-0
 
10.  Petras, J. M., Young, G. D., Bauman, R. A., Kyle, D. E., Gettayacamin, M., Webster, H. K., … Brewer, T. G. (2000). Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: The lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei. Anatomy and Embryology, 201(5), 383–397. https://doi.org/10.1007/s004290050326
11.  Schmuck, G., Roehrdanz, E., Haynes, R. K., & Kahl, R. (2002). Neurotoxic mode of action of artemisinin. Antimicrobial Agents and Chemotherapy, 46(3), 821–827. https://doi.org/10.1128/AAC.46.3.821-827.2002
 
12.  Smith, S. L., Maggs, J. L., Edwards, G., Ward, S. A., Park, B. K., & McLean, W. G. (1998). The role of iron in neurotoxicity: a study of novel antimalarial drugs. Neurotoxicology, 19(4–5), 557–559.
 
13.  Toovey, S. (2006, October 10). Are currently deployed artemisinins neurotoxic? Toxicology Letters. https://doi.org/10.1016/j.toxlet.2006.06.001
 
14.  Brewer, T. G., Peggins, J. O., Grate, S. J., Petras, J. M., Levine, B. S., Weina, P. J., … Schuster, B. G. (1994). Neurotoxicity in animals due to arteether and artemether. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, 33–36. https://doi.org/10.1016/0035-9203(94)90469-3
 
15.  Miller, L. G., & Panosian, C. B. (1997). Ataxia and slurred speech after artesunate treatment for falciparum malaria. New England Journal of Medicine, 336(18), 1328. https://doi.org/10.1056/NEJM199705013361818
 
16.  Franco-Paredes, C., Dismukes, R., Nicolls, D., & Kozarsky, P. E. . (2005). Neurotoxicity Due to Antimalarial Therapy Associated with Misdiagnosis of Malaria. Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America, 40(11), 1710–1711. https://doi.org/10.1086/430180
 
17.  Toovey, S. (2006). A case-control auditory evaluation of patients treated with artemether-lumefantrine. American Journal of Tropical Medicine and Hygeine 74, 939-940. 
 
18.  Hutagalung, R., Htoo, H., Nwee, P., Arunkamomkiri, J., Zwang, J., Carrara, V. I., … Nosten, F. (2006). A case-control auditory evaluation of patients treated with artemether-lumefantrine. American Journal of Tropical Medicine and Hygiene, 74(2), 211–214. https://doi.org/74/2/211 [pii]
 
19.  Hasegawa, C., Kudo, M., Maruyama, H., Kimura, M. (2017). Severe delayed haemolytic anaemia associated with artemether-lumefantrine treatment of malaria in a Japanese traveler. Journal of Infection and Chemotherapy.  In press.  https://doi.org/10.1016/j.jiac.2017.10.008
 
20.  Alkadi, H. O. (2007, November). Antimalarial drug toxicity: A review. Chemotherapy. https://doi.org/10.1159/000109767
 
21.  Ribeiro, I. R., & Olliaro, P. (1998). Safety of artemisinin and its derivatives. A review of published and unpublished clinical trials. Medecine Tropicale : Revue Du Corps de Sante Colonial, 58(3 Suppl), 50–53. Retrieved from http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med4&NEWS=N&AN=10212898
 
 
 

Introduction to ADHD

• ADHD is the most well-known and researched neurodevelopmental disorder of childhood
• Approximately 5-6% of children and 2-3% of adults
• Both genetic and environmental factors are implicated
• The genes that are thought to code for ADHD are involved in the heritability of autism spectrum disorders and Tourette’s disorder
• In general, there are three types of ADHD; Inattentive, Hyperactive and Combined

 
History of Amphetamines

• First synthesized in 1887 and then first marketed in 1932 as a nasal decongestant
• Both amphetamine and methamphetamine were supplied as stimulants for soldiers and prisoners of war in WW II
• In the 1970s FDA made amphetamines schedule II and use declined
• However, increased use with derivatives methamphetamines and MDMA

Pharmacology/Pharmacokinetics:

• Absorption/Distribution/Metabolism/Excretion
  • Absorption – all are rapidly absorbed, with bioavailability that ranges between 60% and 90% depending on the route of administration, peak serum concentrations between 3-6 hours
  • Distribution – most compartments of the body, most are relatively lipophilic and readily cross the BBB, Vd from 3-33 L/kg depending on the substance
  • Metabolism – all are metabolized in the liver, however, the pathway depends on the specific substance, most involve CYP2D6
  • Excretion – renal elimination of the parent compound is substantial, also acidification of the urine can increase elimination, but usually not recommended

 
Therapeutic levels

• Not generally obtained given lack of clinical relevance

 
Significant Drug/Drug Interactions

• MAOI use, as well as linezolid or methylene blue may cause hypertensive crisis

 
Metabolic Pathways and active metabolites

• Depending on the amphetamine, many active metabolites can be formed
• Dealkylation and demethylation are mainly performed by CYP1A2, CYP2D6 and CYP3A4, also performed by flavin monooxygenase

Diagnostic Testing and Laboratories

• Chem 8, EKG and cardiac monitoring/observation for at least 6 hours, depending on presentation
• Can obtain UDS to assess presence of amphetamines, however, clinical exam and history is key
  • Many immunoassays have high rate of false positives and false negatives
  • Many substances are similar to amphetamines and may cross-react with the immunoassay
  • False negatives may occur with MDMA and cathinones
• Can consider further testing including but not limited to CBC, UA, CPK, coagulation studies, CXR, CT scan of the head and LP depending on clinical situation

 
Treatment/Management

• As with all presentations, manage ABCs and gain IV access and place patient on monitor
• Vital signs, rapid glucose and complete physical exam, importantly quickly obtain internal temperature
• Hyperthermia requires rapid external and even potentially internal cooling
• Benzodiazepines are first line for both agitation and hypertension/tachycardia
• If hypertension persists and you have attempted to control agitation with benzos, can considering a-adrenergic antagonists like phentolamine and peripheral vasodilators like nitroprusside and nitroglycerin
• Use antipsychotics with caution, have not been shown to be as effective as benzos and may lower seizure threshold, alter temperature regulation, cause acute dystonia and precipitate cardiac dysrhythmias
• If concerned for rhabdomyolysis, maintain UOP of at least 1-2 mL/kg/h
• Need to be suspicious for body packers and stuffers with these substances, treat accordingly

 
What is Stuttering? What causes it?

• Condition in which the normal pattern, rhythm, or timing of speech is disrupted, may be characterized by repetition and prolongation of words, phrases, and sounds, as well as hesitations or pauses that interrupt speech flow
• Can be developmental, psychogenic, result of a medication effect and secondary to brain injuries

 
Multiple Case Reports Discussing Stuttering Associated with ADHD Medications

• A 1991 case report of a 3 year old with two separate trials of stimulants, each of which resulted in stuttering
  • 2.5 mg BID methylphenidate and then pemoline 9.375 mg
  • After 18 months, no recurrence of stuttering
  • They hypothesized that stuttering a result of increased dopaminergic neurotransmission
• A 2015 case report of a 7 year old trialed on methylphenidate and developed stuttering
  • previously healthy with no family or personal history of speech difficulty or stuttering
  • diagnosed with ADHD and started on 10mg daily of methylphenidate
  • 10 days later developed stuttering, decided to stop medication, and stuttering gone in 7 days
  • They noted that methylphenidate had even been used to treat stuttering in previous cases
  • Case report from 1996 reporting sertraline induced stuttering
    • Sertraline was discontinued, and stuttering stopped
    • Akathisia has been noted to be induced by sertraline and this could be potentially related to serotonergic inhibition of the dopaminergic neurons whose cell bodies are located in the ventral tegmental area versus serotonergic inhibition of the dopamine pathways in the nigrostriatum
    • Needs more research whether this is related to speech abnormalities 

• Similarities between stuttering and dystonia are indicated and can possibly be related to the dopamine system
• A study in a bird model did show a relationship to amphetamine administration and their songs
  • Amphetamine administration increased the stereotypy of syllable structure and sequencing as well as vocal motor repetition
  • Amphetamine increased the degree to which stereotyped sequences of syllables were completed before song determination
  • Dopaminergic activity in cortical and basal ganglia structures found to be elevated in stuttering

​
References

1. Alm PA. Stuttering and the basal ganglia circuits: A critical review of possible relations. Journal of communication disorders. 07/2004;37(4):325-369. doi: 10.1016/j.jcomdis.2004.03.001.
2. Alpaslan AH. Stuttering associated with the use of short-acting oral methylphenidate. Journal of clinical psychopharmacology. 12/2015;35(6):739-741. doi: 10.1097/JCP.0000000000000403.
3. Burd L. Stuttering and stimulants. Journal of clinical psychopharmacology. 02/1991;11(1):72-73.
4. Christensen RC. A case of sertraline-induced stuttering. Journal of clinical psychopharmacology. 02/1996;16(1):92-93.
5. Dopheide JA, Pliszka SR. Attention Deficit/Hyperactivity Disorder. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1861&sectionid=146063877. Accessed February 19, 2018.
6. Jang DH. Amphetamines. In: Hoffman RS, Howland M, Lewin NA, Nelson LS, Goldfrank LR. eds. Goldfrank's Toxicologic Emergencies, 10e New York, NY: McGraw-Hill; 2015. http://accesspharmacy.mhmedical.com.libproxy.lib.unc.edu/content.aspx?bookid=1163&sectionid=65097893. Accessed February 19, 2018.
7. Matheson LE. Catecholaminergic contributions to vocal communication signals. The European journal of neuroscience. 05/2015;41(9):1180-1194. doi: 10.1111/ejn.12885.
8. Rabaeys H. Influence of methylphenidate on the frequency of stuttering: A randomized controlled trial. The Annals of pharmacotherapy. 10/2015;49(10):1096-1104. doi: 10.1177/1060028015596415.

 

​

-This is exceptionally frequent compared to epidemiological data from European countries where atypical parkinsonism accounts for only approximately 5% of all cases
- A higher proportion of patients with atypical parkinsonism (consumed soursop fruit 97%; consumed herbal tea 83%) than patients with Parkinson’s disease (fruit 59%; herbal tea 18%) or control with no Parkinson symptoms (fruit 60%; herbal tea 43%).
-When directly injecting rats for one month with the estimated amounts of annonacin ingested in a year by eating one fruit daily, this induced neurodegeneration in the basal ganglia and mesencephalon (Champy et al., 2004) -As an indication of its potential toxicity, an adult who consumes one fruit or can of nectar a day is estimated to ingest over 1 year the amount of annonacin that induced brain lesions in rats receiving purified annonacin by intravenous infusion.
-Multiple studies showing toxicity in vitro to dopaminergic neurons
-Cultured neurons treated with low doses of annonacin exhibit hallmarks of tauopathy, including increased tau concentration, tau hyperphosphorylation, cell death and somatodendritic redistribution of hyperphosphorylated tau which is that same pathophysiology of progressive supranuclear palsy.
-Studied as a cytotoxic agent for use in cancer chemotherapy
-Extract from the seeds and leaves have IC50 comparable to doxorubicin at .57μg/mL (seed) and .36μg/mL (leaves) compared to .11μg/mL (doxorubicin) in leukemia cells.
-Mechanism of action is via annonacin, the acetogenin causing mitochondrial membrane potential disruption. It inhibits NADH dehydrogenase on Complex I of the electron transport chain. Creates reactive O2 species that can damage DNA and other components of mitochondria
-Annona muricata leaf extract reduced the tumor's size and weight, showed anti-metastatic features, and induced apoptosis in vitro and in vivo of the 4 T1 breast cancer cell lines. Furthermore, it decreased the level of nitric oxide and malondialdehyde in tumor while also increased the level of white blood cell, T-cell, and natural killer cell population. 

​

Pharmacology
-LD 50 >2g/kg
-In IV administration to Rats 3800 and 7600 μg/kg daily caused neurodegeneration over a period of 28 days -it appears that chronic consumption causes the neurodegeneration
​
Presentation
-Levodopa resistant parkinsonism similar to progressive supranuclear palsy
-PSP presents with loss of balance, bradykinesia, rigidity, problems controlling eye movements, issues with speech and swallowing
-Patients in Guadaloupe:
-early postural instability
-supranuclear oculomotor dysfunction
-greater frequency of patients with tremor as compared to typical PSP
-greater frequency of patients with hallucinations as compared to typical PSP

Laboratories
-no laboratory evidence of annonacin toxicity
-annonacin can be identified in brain neurons on autopsy

Treatment/Management
-stop ingestion of soursop
-poor response to levodopa or other parkinson’s treatment agents 

​