Theophylline Toxicity:

Does the diagnosis matter in

the management of acute toxicity?
A case report of survived undiagnosed patient presented to
the Emergency Department, HUSM

3rd Clinical Conference on Emergency Medicine

Kota Kinabalu, Sabah
23-25 April 2009

Nasir M*, Nurkhairul NAH*, Kamarul AB*, Chew KS*

Rashidi A*, Ismai R**
*Emergency Medicine Rsearch Group,Department of
Emergency Medicine, School of Medical Sciences, USM
Health Campus, Kelantan, Malaysia.** Pharmacogenetic
Research Group, Institute For Research In Molecular
Medicine, USM Health Campus, Kelantan, Malaysia.
Outlines
 Case study
 Overview: Theophylline
 Related journals
 Pathophysiology

 Pharmacokinetics

 Toxidromes
 Management: measures to be taken
 Conclusion
 References
 We present a case of attempting suicide
who sustained generalised tonic-clonic
seizures and supraventricular tachycardia.
 As this was our first experience
encountering such a case, we recommend
a few measures to be taken especially
when managing patient with undiagnosed
toxidrome in our emergency department.
Case discussion
 A 22/ED/HUSM/10 H/ ? ingesting 30
tablets of antihistamine.
 Intermittent nausea and non projectile
vomiting.
 complained of epigastric pain 2 hours post
ingestion
Physical Examination
 He was drowsy, tachypnoeic, tachycardic
(120 bpm), borderline hyopotensive (90/64
mmHg) and normothermia with moist skin
 The pupils sizes were 3mm EB and RTL.
 The lower abdomen was distended.
 Other systems were unremarkable.
 ECG showed sinus tachycardia
 RBS 6.7mmol/l.
Initial ED Management
 iv metochlopramide 10 mg as well as iv
ranitidine 50 mg was administrated
 Activated charcoal was initiated.
 500 cc iv bolus crystalloid was
administered but the BP was still
hypotensive.
 iv noradrenalin was started to restore the
blood pressure.
 Progress of patient in ED
 After 2 hours in ED, patient suddenly developed
generalized tonic-clonic seizure twice. Each
episode lasted 10 minutes
 Fit was aborted after iv valium 5mg bolus was
admistered.
 He was prophylactically given iv phenytoin to
prevent further fit
 He was electively intubated for airway protection
and cerebral resuscitation.
 Initial blood gases noted to be metabolic alkalosis,
and he was hypokalemic (refer Table 1).
Table 1: Serial ABG result

Day/time (Immediate) Post ET 2 3 4 5 6 7

pH 7.475 7.188 7.339 7.192 7.44 7.44 7.395 7.427

pCO2 (mmHg) 34.2 27.3 23.1 36.6 22.2 19.2 32.9 50.2

pO2 (mmHg) 291 56.5 187 181 195 63.4 165 84.3

Base excess 1.6 -16.6 -12.6 -13.1 -8.5 -10.5 -4.9 -8.0

HCO3 26.4 12.1 15.1 14.1 18.6 17.0 20.9 32.5

 Serial pH results

7.5
7.45
7.4
7.35
7.3
pH

7.25
7.2
7.15
7.1
7.05
7
0 1 2 3 4 5 6 7
Days of admission
 Patient was admitted into (ICU) for
monitoring and supportive care.
 In ICU, he developed supraventricular
tachycardia (SVT) with unstable
haemodynamics and synchronized
cardioversion 50J was delivered
 His rhythm was successfully reverted to
sinus rhythm.
 Patient was self extubated at day-2 of
hospitalization
 The BP was normotensive on inotrops and
the PR remains tachycardic.
 He sustained acute renal failure and was
referred to nephro team for HD but he was
treated consecutively.
Table 2: Serial Theophylline level

Serial Theophyline Level

45

Time ( hours) Serum theophylline level 40

72 40. 4µg/ml 35

30

Serum Theophyline
96 20.5µg/ml
25

120 2.83µg/ml 20

15

10

0
72 96 120
Hours
Table 3: Serial BUSE

Day 1 2 3 4 5 6 7 8 9 10

Urea(mmol/l) 8.0 8.0 14.5 18.7 16.3 29.5 32.9 35.4 31.3 31

K (mmol/l) 2.6 3.0 4.8 5.7 5.1 4.9 5.0 4.4 4.3 4.0

Na (mmol/l) 132 137 145 147 152 151 154 153 148 148

Creat (mmol/l) 160 178 307 367 373 574 603 577 530 501
 Further history elicited from patient after
he regained his consciousness, revealed
that he took 30 tablets of neulin SR 250
mg.
 Discharged well after 2 weeks
hospitalization.
Teophylline: An Overview.
Introduction

 Theophylline is a commonly used drug in the treatment

of acute or chronic lung diseases.
 Theophylline poisoning is a toxicological emergency
 It has a narrow therapeutic index with erratic absorption
and elimination contribute to toxicity with high morbidity
and mortality.
 Drugs included in this group:
 Aminophylline & Theophylline
 Theophylline’s toxidrome may be overlapping with other
drug toxicity especially in un-witnessed patient with
altered higher mental functions.
 Journals related to
Theophylline toxicity:
 Pub Med: 24
 Drug screening of patients who deliberately harm themselves admitted to the emergency department .Ther
Drug Monit. 1998 Feb;20(1):98-103.. Skelton H, Dann LM, Ong RT, Hamilton T, Ilett KF.
 Treatment of acute asthma. Lack of therapeutic benefit and increase of the toxicity from aminophylline
given in addition to high doses of salbutamol delivered by metered-dose inhaler with a spacer. Rodrigo C,
Rodrigo G.Chest. 1994 Oct;106(4):1071-6.PMID: 7924475 [PubMed - indexed for MEDLINE]
 The clinical implication of theophylline intoxication in the Emergency Department. Tsai J, Chern TL, Hu SC,
Lee CH, Wang RB, Deng JF.Hum Exp Toxicol. 1994 Oct;13(10):651-7.PMID: 7826681 [PubMed - indexed
for MEDLINE]
 Theophylline toxicity.Cooling DS.J Emerg Med. 1993 Jul-Aug;11(4):415-25. Review.PMID: 8228104
[PubMed - indexed for MEDLINE
 Severe theophylline toxicity in a pregnant asthmatic patient] .Nagahama H, Nagano K, Yamanaka I,
Kasagawa J, Seki I, Suzuki Y.Masui. 1993 Jul;42(7):1076-80. Japanese. PMID: 8350478 [PubMed -
indexed for MEDLINE]
 Failure of gastric emptying and charcoal administration in fatal sustained-release theophylline overdose:
pharmacobezoar formation.Bernstein G, Jehle D, Bernaski E, Braen GR.Ann Emerg Med. 1992
Nov;21(11):1388-90.PMID: 1416337 [PubMed - indexed for MEDLINE
 Aminophylline in the emergency department. Maximizing safety and efficacy.Kino R, Day RO, Pearce GA,
Fulde GW.Chest. 1991 Dec;100(6):1572-7.PMID: 1959397 [PubMed - indexed for MEDLINE]
 Theophylline toxicity secondary to ciprofloxacin administration.Spivey JM, Laughlin PH, Goss TF,
Nix DE.Ann Emerg Med. 1991 Oct;20(10):1131-4.PMID: 1928889 [PubMed - indexed for
MEDLINE]
 Severe lactic acidosis following theophylline overdose.Bernard S.Ann Emerg Med. 1991
Oct;20(10):1135-7.PMID: 1656819 [PubMed - indexed for MEDLINE
 Theophylline
intoxication, clinical features, treatment and outcome: a case report and a review of the
literature.Stegeman CA, Jordans JG.Neth J Med. 1991 Aug;39(1-2):115-25. Review.PMID:
1961347 [PubMed - indexed for MEDLINE
 Inpatient theophylline toxicity: preventable factors.Schiff GD, Hegde HK, LaCloche L, Hryhorczuk
DO.Ann Intern Med. 1991 May 1;114(9):748-53.PMID: 1953845 [PubMed - indexed for MEDLINE
 Risk of toxicity in patients with elevated theophylline levels.Emerman CL, Devlin C, Connors
AF.Ann Emerg Med. 1990 Jun;19(6):643-8.PMID: 2344081 [PubMed - indexed for MEDLINE]
 Theophylline toxicity: clinical features of 116 consecutive cases.Sessler CN.Am J Med. 1990
Jun;88(6):567-76. Review.PMID: 2189301 [PubMed - indexed for MEDLINE
 Poor tolerance of oral activated charcoal with theophylline overdose.Sessler CN.Am J Emerg
Med. 1987 Nov;5(6):492-5.PMID: 3663290 [PubMed - indexed for MEDLINE]
 Rapid assay of serum theophylline levels.Reinecke T, Seger D, Wears R.Ann Emerg Med. 1986
Feb;15(2):147-51.PMID: 3946856 [PubMed - indexed for MEDLINE]
 Treatment of theophylline toxicity with oral activated charcoal.Sessler CN, Glauser FL, Cooper
KR.Chest. 1985 Mar;87(3):325-9.PMID: 3971756 [PubMed - indexed for MEDLINE]
Pathophysiology
 Excessive ß-adrenergic activity
 Phosphodiesterase Inhibitor causes increased intracellular cAMP (ß-adrenergic
mediators) and beta adrenergic activity
 Directly stimulates adrenal medulla to excrete catecholamine.
 Peripheral venodilatation, increase cardiac output, natriuresis, gastrin release
and H prroduction, gluconeogenesis, etc

 Metabolic abnormalities
 Induced Intracellular shift of K
 hypoK, Metabolic Acidosis, Respiratory Alkalosis, Hyperglycaemia
 intracellular calcium translocation

 The blockade of adenosine receptors

 Negative feedback to the heart in situations of sympathetic overstimulation.

 CNS toxicity
 Overstimulation Mechanism is unclear- agitated, hyperreflexia, fit
 Increase cerebral vasoconstriction due to –ve inhibition
 Increase cAMP is an eliptogenic, it reduces the seizure threshold and increase
paroxysmal activity on EEG
Pharmacokinetics
 Absorption
 Conventional preparations exhibit virtually complete and rapid
absorption (peak concentrations 0.5-2 H).
 Therapeutic doses of sustained release preparations vary in the total
extent of absorption and in the time to peak concentration (4-18 H).
 In acute poisoning with sustained release preparations the peak
concentration usually occurs between 2 and 18 H after admission but
can occur up to 24 H.
 Distribution
 Vd is 0.5 L/kg and in normal adults the clearance is 40-45 mL/kg/hr
giving a half-life of approximately 8 hours.
 Metabolism - Elimination
 In overdose, hepatic metabolism of theophylline is frequently saturated
& the apparent half-life can be as long as 30 hours.
 The pharmacokinetics of theophylline may be further affected by
intercurrent hepatic, cardiac or renal disease and numerous medications
Clinical Presentation
 2 types:
 Acute Intoxication Tolerate higher levels of the drug

 Intentional Overdose
 Metabolic derangement
 Does not demonstrate adverse effects until the
Level >100mg/L

 Chronic Intoxication:
 Manifest serious effect as low as 40mg/L
Discussion:
10-hours post-ingestion:
 Abdominal pain, urinary retention, nausea, vomiting, normal
body temperature and normal pupils sizes with altered mental
status, hypotension, sinus tachycardia and subsequently
developed generalized tonic-clonic seizure and SVT

Possible diagnosis:

 Sympathomemetic toxicity

 Antidepressant toxicity

 Anticholinergic toxicity
 the points that against it were hypotension, moist skin with normal body
temperature and the normal pupils’ sizes and hypokalaemia)
Other Toxidromes
Potentially Toxic Drugs: by Type of Cardiopulmonary Signs* of Toxicity Therapy to Consider†
Agent
Stimulants (sympathomimetics) • Tachycardia • Benzodiazepines
• Amphetamines • Supraventricular arrhythmias • Lidocaine
• Methamphetamines • Ventricular arrhythmias • Sodium bicarbonate (for cocaine-related
• Cocaine • Impaired conduction ventricular arrhythmias)
• Phencyclidine (PCP) • Hypertensive crises • Nitroglycerin
• Ephedrine • Acute coronary syndromes • Nitroprusside
• Shock • Reperfusion strategy based on cardiac
• Cardiac arrest catheterization data
• Phentolamine (_1-adrenergic blocker)
• _-Blockers relatively contraindicated (do
not use propranolol for
cocaine intoxication)
Calcium channel blockers • Bradycardia • NS boluses (0.5 to 1 L)
• Verapamil • Impaired conduction • Epinephrine IV; or other _/_-agonists
• Nifedipine (and other dihydropyridines) • Shock • Pacemakers
• Diltiazem • Cardiac arrest • Circulatory assist devices?
• Calcium infusions
• Glucose/insulin infusion?
• Glucagon
Adrenergic receptor antagonists • Bradycardia • NS boluses (0.5 to 1 L)
• Propranolol • Impaired conduction • Epinephrine IV; or other _/_-agonists
• Atenolol • Shock • Pacemakers
• Sotalol • Cardiac arrest • Circulatory assist devices?
• Metropolol • Calcium infusions?
• Glucose/insulin infusion?
• Glucagon
Tricyclic antidepressants • Tachycardia • Sodium bicarbonate
• Amitriptyline • Bradycardia • Hyperventilation
• Desipramine • Ventricular arrhythmias • NS boluses (0.5 to 1 L)
• Nortriptyline • Impaired conduction • Magnesium sulfate
• Imipramine • Shock • Lidocaine
• Cardiac arrest • Epinephrine IV;
Cardiac glycosides • Bradycardia • Restore total body K_, Mg__
• Digoxin • Supraventricular arrhythmias • Restore intravascular volume
• Digitoxin • Ventricular arrhythmias • Digoxin-specific antibodies (Fab
• Foxglove • Impaired conduction fragments: Digibind or DigiFab)
• Oleander • Shock • Atropine
• Cardiac arrest • Pacemakers (use caution and
monitor for ventricular
arrhythmias)
• Lidocaine
• Phenytoin?
Anticholinergics • Tachycardia • Physostigmine
• Diphenhydramine • Supraventricular arrhythmias
• Doxylamine • Ventricular arrhythmias
• Impaired conduction
• Shock, cardiac arrest
Cholinergics • Bradycardia • Atropine
• Carbamates • Ventricular arrhythmias • Decontamination
• Nerve agents • Impaired conduction, shock • Pralidoxime
• Organophosphates • Pulmonary edema • Obidoxime
• Bronchospasm
• Cardiac arrest
Opioids • Hypoventilation (slow and shallow • Assisted ventilation
• Heroin respirations, apnea) • Naloxone
• Fentanyl • Bradycardia • Tracheal intubation
• Methadone • Hypotension • Nalmefene
• Morphine • Miosis (pupil constriction)
Sodium channel blockers (Class IV • Bradycardia • Sodium bicarbonate
antiarrhythmics) • Ventricular arrhythmias • Pacemakers
• Procainamide• Propafenone • Impaired conduction • Lidocaine (not for lidocaine
• Disopyramide• Flecainide • Seizures overdose)
• Lidocaine • Shock, cardiac arrest • Hypertonic saline
Does the diagnosis matter
in the acute management?
 Important Questions…..
 Does toxidrome identification affects the initial management at the ED
 What is our management strategy?
 History does not compatible with clinical toxidromes. …
 Any role of gastric lavage in case of more than 1 hour post intoxication?
 Any role of activated charcoal or Multi-doses Activated Charcoal?

 Any role of
 Metoclopramide ?
 Ranitidine ?

 Is there any inter-variability of pharmacokinetics?

 In overdose, hepatic metabolism of theophylline is frequently saturated & the
apparent t½ can be as long as 30 H.
 CYP 450 polymorphisms affect the metabolisms
 It is further affected by
• intercurrent hepatic
• cardiac
• renal disease
• numerous medications
Important Distinction

 Which toxidrome the patient had?

 Rule out:
 Alcohol, Bdz, Stimulants, PCM, TCA, Salicylate, etc
 If strongly suspected: Thophylline, Anticholinergic,
Cholinergic, etc.
 Toxicity from an acute single ingestion or from
chronic overmedication.
 A sustained release preparation or not ?
 Gastric pharmacobenzoar formation?
Early Measures to be Taken
While Attempting
Acute Intoxication…
Management Decisions
 Based on both
 Clinical
Assessment
 Laboratory Information
 (eg..theophylline concentrations).

 Efforts toward achieving successful

detoxification.
 Frequent observation
 Aggressive efforts
Determination of Severity
 Over treat versus under treat?
 All patients require frequent clinical assessment of their
severity.
 The history should establish
 The time of ingestion
 The dose and type of preparation (sustained release or
conventional)
 Whether the poisoning is acute or chronic
 General history with emphasis on diseases which may
increase patient's susceptibility to major theophylline toxicity
(e.g. cardiac or neurological disease) or alter theophylline
pharmacokinetics (e.g. hepatic disease).
 Concomitant drug therapy should be recorded
 Clinical Features of Severity
*The most serious category should be assumed.

Mild Moderate Severe

Vomiting but tolerates
Nausea Vomiting & not tolerating decontamination
decontamination

Pulse < 120 Pulse < 140 pulse >140

Systolic BP > 120 mmHg Systolic BP > 100 mmHg Systolic BP < 100 mmHg
No arrhythmias Atrial or ventricular ectopics SVT or Ventricular Tachycardia
. Agitation or hyperreflexia Seizures
. Potassium < 3.0 mmol/L Potassium < 3.0 mmol/L
. Glucose > 10 mmol/L Glucose > 10 mmol/L
Rising 2nd hourly theophylline concentrations in the
.  
presence of apparently effective decontamination

Potentially significant toxicity includes:

1. All Chronic Overmedication,
2. Acute Ingestions of > 10 mg/kg,
3. Acute ingestions with more than mild toxicity regardless of stated amount ingested.
Treatment
 Supportive
 Control of vomiting
 GI decontamination
 Treatment of specific complications
 Central nervous system
 Cardiac
 Metabolic effects
 Elimination enhancement
 Multidose charcoal
 Charcoal haemoperfusion
 Haemodialysis
General Measures
 Basic Supportive:
 Airway Management
 Oxygen administration

 Haemodynamics monitoring

 Intra-venous access

 Symptomatic support
Correction of Hypotension
 Peripheral ß2 ADR and venodilation
 Bolus 250-500mls of crystalloid
 Pharmacologic:
 α-agonist:phenylepidrine or NA/ adrenalin
 Non-selective ß2 ADR blockade: propranolol
Antiarrhythmias
 Supraventricular dysrhythmias (ST, SVT,MFAT,AF)
 ß-blocker:
propranolol infusion
 Ca Channel Blocker: verapamil

 Ventricular dysrhythmias
K correction
 Lignocaine/Amiodarone
Anticonvulsants
 To stop seizures:
 Benzodiazepine
 Phenobarbitone
 Phenytoin

 Role of general anaesthesia (GA) and

muscle relaxant:
 to facilitate ventilation
 to protect the airway and cerebral resuscitation
 to prevent acidosis and rhabdomyolysis.
GI Symptoms
 Nausea and Vomiting
 Dyspepsia
 Abdomen pain
 Metoclopramide

 Ondansetron
GI Decontamination
 Gastric Lavage controversies
 1H : indicated
 3-4 H : sustained release
 Theophylline toxicity: depends on preparation
 Restricted to poisonings where benefits over oral activated charcoal
are likely.
 should be considered in
 Potentially life-threatening poisoning (or history is not available) and
unconscious presentation √
 Potentially life-threatening poisoning and presentation within 1 hour
 Potentially life threatening poisoning with drug with anticholinergic effects
and presentation within 4 hours
 Ingestions of sustained release preparation of significantly toxic drug √
 Large salicylate poisonings presenting within 12 hours
 Iron or lithium poisoning
The Position Statement :
1.American Academy of Clinical Toxicology
2.European Association of Poisons Centres & Clinical Toxicologists.

 Gastric lavage should not be employed routinely in the management

of poisoned patients.
 In experimental studies, the amount of marker removed by gastric
lavage was highly variable and diminished with time.
 There is no certain evidence that its use improves clinical outcome
and it may cause significant morbidity.
 Gastric lavage should not be considered unless a patient has
ingested a potentially life-threatening amount of a poison and the
procedure can be undertaken within 60 minutes of ingestion.
Elimination Enhancement
 1. Multiple Doses Activated Charcoal (MDAC)
 All patient
 to double the clearance of theophylline, being as effective
as a haemodialysis.
 0.6-1g/kg or 10 g of charcoal for every gram of theophylline
ingested.
 2 H charcoal administration will dramatically reduced the t½

 2. Charcoal Hemoperfusion
 the most effective, increasing clearance 4- to 6-fold.
 Theophylline level of:
 90-100 mg/L
 60 mg/L
 3. Hemodialysis/ Peritoneal Dialysis
 Med Toxicol Adverse Drug Exp. 1987 Jul-Aug;2(4):294-308
Take Home Messages……
Conclusion
 To gain a better outcome requires :
 Adequate history
 Adequate Assessment: Thorough PE-identify toxidrome
 Rule out: Alcohol, Bdz, Stimulants, PCM, TCA, Salicylate, etc
 If strongly suspected: Thophylline, Anticholinergic, Cholinergic, etc.

 Approach of management:
 Assess vital signs
 Identify pathophysiology changes
 To correct underlying pathological process: ABC
 Early serum toxicology screening based on high index of suspicion

 Always have a 2nd opinion in case of doubt.

 A good knowledge on toxicology

 Pharmacokinetics
 Pharmacidynamics
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Thank you…………..