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Figure 1

Lessons from a Histrory that Can’t be Ignored

Editors Message: Scientific committee Toxicology, as history shows is important for obvious reasons, especially for those who come into close contact with it. Advancement in this field is rapid, and it comes true only when you engage yourself in all matters of life. After all, toxicology is the science of life. One can say "it is a skull and a cross bone". This can't really tell the whole story about toxicology; it is quite not true, because this discipline tackles various issues in life. Through history, prominent figures have changed the face of toxicology, like Paracelsus (Auroleus phillipus; 1493 – 1541) who sometimes referred to as 'the father of toxicology'. He wrote the famous ever-lasting quote: "all things are poisons, and nothing is without poison; only the dose permits something to be poisonous", in other words "the dose makes the poison", which is basically one of toxicology fundamentals. Mathieu Orfilla, the father of modern toxicology, had given the subject its formal treatment in 1813 in his "traite de position" or "toxicology general". In his book, he summarized everything known about poisons and gave them their classifications. He used several tests for poison detection, and found that some are not reliable and pursued to find more accurate tests. Additionally, he used animal testing. This led him to be acknowledged as a trustworthy scientist and eventually he was trusted enough to be consulted in criminal cases. The special thing about Orfilla was; that he had an intuition when toxicology was not yet a real science that it could become a science that matters. Even in the History of the Islamic Scientific Renaissance, when toxicology was part of Alchemy and pharmacy. A universal scholar who had an extensive knowledge studied toxicology extensively; a genuine polymath flourished during the second half of the eighth century C.E. "Jaber Ibn Hayan". Toxicology was manifested in his book of poisons; a book of poisons and antidotes. This breakthrough in life, starting from identifying the poison, dose, treatment and prevention are what toxicology is all about. When poisons are said to be the stealth killers of the era, understanding and comprehension of the science of toxicology will be the remedy. And definitely Toxicology is a milestone in science, where life issues, environment and laws collide.

Theme of the month

Captagon: A drug of Vigilance or a way of self destruction

1.1 The truth behind Captagon trafficking. Jordan Status Update

The officers in the management of Anti-Drug Trafficking have foiled a smuggling process of half a million Captagon drug tablets on late January 2012 in one of the areas of the capital Amman.

The Information Officer in the PSD (Public Security Directorate/ Anti-Narcotics Department) said in a statement issued after that: the Drug Enforcement Administration (DEA) had received information that a group of people were in possession of a large quantity of sleeping pills and were trying to smuggle and to take them out of the country. The statement continued; after the follow-up of these people they were identified of their identity. Then, the time was determined accurately for the work to be held. Police ambushes were needed to raid the specified location and adjust the amount in possession of these pills. The two people who were involved were captured and prosecuted (1).

As such events, authorities in Jordan are intercepting and seizing millions of tablets marketed as Captagon every year.

Captagon is classified by the United Nations Office on Drugs and Crimes (UNODC) as amphetamine- type stimulant. It was banned in Jordan in 1988. This drug has acquired significant popularity in the Arabian Gulf region, other countries in the Middle East as well as South-West Asia; the last represents the main source of amphetamine seizures according to the UNODC. Bulgaria and Turkey are believed to be the main source of Captagon, which is trafficked through Syria into neighboring countries, including Jordan. From there it is taken into Saudi Arabia and the whole Arabian Peninsula (2) figure 1. Jordan have faced a striking increase in amphetamine group tablets and Amphetamine type stimulants (ATS) seizures since 2003, and according to the UNODC tablet seizures have increased to more than one third over the year 2007, figure 2. Higher rates were recorded in crimes and in the number of drug users, in particular among young people and adolescents who were drawing the attention of responsible authorities and the health sector. All of that mean that drug use is proliferating and becoming one of the preferred drugs among affluent population vastly and under several street names like: .(منشطط االسووااقة ,منشطط االددررااسة ,أأبوو هھھھالليینن , كبتت ,كبتاغوونن ) Even though Captagon’s clandestine and counterfeit are not a new phenomenon in Europe and other countries, there are currently no indications that Jordan will move from a predominantly drug- transient to a drug- producing country according to Jordanian PSD (2).

Issue No: 2

Quarterly Newsletter

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TOXICOLOGY A NEW ERA OF SCIENCE TO PRACTICE

Figure 2

References

1. Alghad News paper, February issue 2012 2. UNODC world drug report 2010

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Issue No: 2

Quarterly Newsletter

2. Editors Appraisal

FACTS

• Jordan is a party in the 1988 UN drug convention, and in The 1971 UN convention on psychotic substances.

• Existing laws prohibit the cultivation and production of narcotics and ATS in Jordan; these laws have been effectively enforced.

• Jordan remains primarily a transient country, and Jordan's main challenge in stemming the flow of illicit drugs through the country remains its vast and open desert borders.

• Since 2001, the Jordanian Government in conjunction with the UNODC has strengthened treatment and rehabilitation services for drug abusers in Jordan.

1.2 Captagon Captagon is the trade name of Fenethylline; 7-(2-α – methylphenyl-aminoethyl)-theo-phylline, which is an N – alkylated amphetamine derivative (paper, case). It is metabolized to form amphetamine (24.5% of the oral dose) and theophylline (13.7% of the oral dose); both of which are marked by being active stimulants (1). Fenethylline is a central nervous system stimulant with an effect similar to amphetamine and it does not have an accepted medical use any more. It was used in patients with attention deficit hyperactivity disorder (ADHD), narcolepsy and depression. Fenethylline misuse started early in 1970 and It was believed to have less side effects and less abuse potential than amphetamine (2). However the effect on the abuser is generally a combination of the effects of amphetamine and theophylline as well as fenethylline. When taken in small to moderate doses, amphetamine produces the following effects: tachycardia, hyperpyrexia, tachypnia (hyperventilation) and hypertension. In addition, a user initially experiences dilation in bronchial vessels, becomes highly- energized and anorectic. Long-term side effects of amphetamine use, however, include but are not limited to: major depression, lethargy, insomnia, cardiotoxicity and malnutrition. Collectively, hypertension and tachycardia are the most common effects. Psychosis usually occurs at large doses only, but it has been known to occur also in children taking therapeutic doses for the treatment of ADHD (1). Theophylline use is complicated by the fact that it interacts with various drugs. It can also cause nausea, diarrhea, tachycardia, arrhythmias, and CNS excitation (headaches, insomnia, irritability, dizziness and lightheadedness). Theophylline toxicity is enhanced by certain medications, such as erythromycin, cimetidine, and ciprofloxacin. Al. Ghadyan 2009 reported three cases of hemorrhagic central retinal vein occlusion following continuous use of fenethylline hydrochloride. The hemorrhage, the edema and the engorged veins showed marked improvement after discontinuing the drug and laser treatment in one case (3) It is irrational to say that Captagon effect is 100% due to the aforementioned three substances, because it is well known that licit Captagon tablets are not available nowadays and what is available at present may contain Fenethylline or a combination of substances that mimic its effect. References: 1. Kristen, G., Schafer, A., Schlichtegroll, 1986. Fenethylline: therapeutic use, misuse, and or abuse. Drug Alcohol Dependence, 17, 259 – 271. 2. Ulucay, A., Kargi, C.A., Akosy, M. F. 2012. Acute myocardial infarction associated with captagon use. Anadolu Kardiyol Derg. 12(1). 3. Al-Ghadyan, A A Rushood and A A Alhumeidan, 2009. Fenethylline as a possible etiology for retinal vein occlusion , Ann Ophthalmol (Skokie) 41(3-4):199-202.

Table 1: Substances found in counterfeited Captagon when detected by GC-MS (Al. Abdallah 2005) substance Substance induced

physiological activity Amphetamine Stimulant

Methamphetamine Stimulant

Ephedrine Sympathomimetic

Metronidazole Antiamebic

Caffeine Stimulant

Theophylline Vasodilator

Chlorphenamine Antihistamine

Procaine Local anesthetic

Trimethoprim Antibiotic

Chloroquine Anti malarial

Quinine Anti malarial

Figure 1; Photograph of a tablet produced in Serbia used in counterfeit

The existence of the synergistically- acting amphetamine, Caffeine, quinine and so many other ingredients in one tablet, as well as the distinctive color and logo, strongly imply that all seized quantities which intended for the illegal market as surrogate for Captagon are representing an imminent danger to the youthful generations, on one side, who are unaware of the disastrous complications which might rise from one tablet, and to the physicians, on the other side, who can't even guess what are the ingredients, of this illicit Captagon tablet as they stand unintentionally idly to such a problem.

References: Al. Abdalla, M.A. 2005. Chemical Characterization of counterfeit captagon tablets seized in Jordan, Forensic science international, 152, 185 – 188.

1.3 Captagon: is it really fenethylline

Recent studies have revealed that the tablets seized by authorities in Jordan and neighboring countries as counterfeiter, under the trade mark CAPTAGON "Fenethylline", often contained different ingredients that generally induced effects similar to those of Fenethylline. They also had the same shape, and sometimes the color of the original product (figure 1).

This was enforced by Physical and chemical tests that were used to characterize these tablets in comparison with the authentic product, which is rarely found in its original form since banning in 1988. Usually counterfeit tablets contain: amphetamine, Caffeine, ephedrine, quinine, theophylline, acetaminophen, diphenhydramine and lactose, or just a combination of all. A study was conducted in Jordan by Alabdallah, 2005 at the Forensic Labs. After analyzing 124 batches of Captagon seized and analyzed by Gas Chromatography- Mass Spectrometry (GC- MS). His study revealed the absence of fenethylline in all samples analyzed. Instead of it, GS-MS has detected the presence of the following substances that induced the same effects of fenethylline (see table 1)

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Issue No: 2

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3. Case study A 21-year-old male was admitted to the emergency department with chest pain. The patient collapsed during initial examination. Cardiac monitoring showed ventricular fibrillation. So, defibrillation was carried out immediately. Electrocardiogram (ECG) showed widespread ST segment, elevation in anterolateral leads with reciprocal changes in inferior leads confirming AMI.

Initial medical procedures or drugs administered on admission

Drug dose

Acetyl Salicylic Acid (ASA) 300 mg Oxygen unfractionated heparin bolus 5000 units Heparin infusion Emergency Percutaneous Coronary Intervention (PCI)

On admission, he was confused, aggressive with strange behavior. Medical history according to his relatives didn't reveal any cardiovascular risk factors other than smoking.

Physical examination Diagnostic Measure

Result

Blood Pressure (BP) 115/ 70 mmHg

Heart Rate (HR) 90 beats per minute (bpm)

Cardiac and respiratory examinations

Unremarkable

Presence of some old self-mutilation scars on arms and

chest wall

Repeated ECG Normalization of ST segment changes in anterolateral leads

Neurological consultation for mental state and behavioral evaluation

No objective evidence of any disease

Cranial computed tomography (CT) scan

Normal

A primary PCI was deferred, so he was agitated and had normalization of ST changes on ECG (Fig. 2). The patient's agitation was controlled by haloperidol.

Initial Laboratory test

Value Normal value

Creatine Kinase (CK)

344 units/liter (U/L)

Reference range: 24-195 (Normal levels in men = 38-174 U/L. Normal levels in women= 96- 140 U/L)

Troponin I (TnI)

0.616 ng/mL

cut–off value in laboratory: 0.4 ng/mL

He was then transferred to the coronary intensive care unit and Maintained on the following medications:

Drug Dose

Haloperidol (3 mg/day) ASA (300 mg/day) clopidogrel (75 mg/day) metoprolol succinate (25 mg/day) atorvastatin calcium (10 mg/day) intravenous nitroglycerin infusion

(5 mcg/minute, titrated doses on his blood pressure response)

unfractionated heparin infusion

(under activated partial thromboplastin time control)

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The following day, his mental status was considered as normal, and haloperidol therapy was withheld. Investigations including lipid profile, homocysteine, thyroid and kidney function tests along with blood sugar levels revealed normal results. Search for connective tissue disorders and vasculitic syndromes were unremarkable. Abnormal laboratory results showed: leukocytosis, elevated levels of serum aspartate aminotransferase and cardiac enzymes. His cardiac enzyme markers peak levels were: CK of 1513 U/L and TnI of 18.7 ng/mL. Because of recurrent chest discomforts on the third day of his admission, a coronary angiography was planned and performed. It showed a significant narrowing in the proximal portion of the left anterior descending (LAD) artery (Fig. 3). The circumflex and the right coronary arteries were normal. Significant narrowing in the proximal portion of the LAD persisted despite repeated doses of intracoronary nitroglycerin (total of 200 micrograms). A bare metal direct stenting * was performed on this lesion, with a residual 10% narrowing (Fig. 4). A high pressure, nominally sized balloon post dilatation was performed for optimizing stent expansion and resulted in rupture of the balloon. Neither vessel perforation nor dissection was occurred on or near the stented segment. Final angiography showed a satisfactory result. The following day, to clarify the patient's medical history, a further attempt was performed. He confessed of taking a pills of Captagon prior to chest discomfort. Hence, No urine screen for illicit drugs' metabolites was performed. A transthoracic echocardiographic examination was performed before the patient discharged from hospital. The left ventricular ejection fraction was estimated to be about 50%, and there was only mild hypokinesia of the anterior segments. He was discharged on the fifth day on 300 mg of oral (ASA), 75 mg of clopidogrel, 2.5 mg of perindopril daily, with instruction to avoid using any illicit drugs in the days to come. Conclusion: Although acute myocardial infarction (AMI) is usually a disease of older ages, it may be seen in younger ages. In young cases of AMI non atherosclerotic coronary artery disease (CAD), thrombophilia, illicit drug abuse, premature atherosclerosis must be considered. Illicit drug abuse such as amphetamines and cocaine has been widely recognized as a causative agent in AMI. Abuse of fenethylline as the brand Captagon may also cause AMI