Cardioprotective effect of pioglitazone in diabetic and non-diabetic rats subjected to acute myocardial infarction involves suppression of AGE-RAGE axis and inhibition of apoptosis.

Insulin resistance increases risk of cardiovascular diseases. This work investigated the protective effect of pioglitazone on myocardial infarction (MI) in non-diabetic and diabetic rats, focusing on its role on advanced glycated endproducts (AGEs) and cardiac apoptotic machinery. Male rats were divided into 2 experiments: experiment I and II (non-diabetic and diabetic rats) were assigned as saline, MI (isoproterenol, 85 mg/kg, daily), and MI+pioglitazone (5, 10, and 20 mg/kg). Injection of isoproterenol in diabetic rats produced greater ECG disturbances compared to non-diabetic rats. Treatment with pioglitazone (5 mg/kg) reduced the infarct size and improved some ECG findings. Pioglitazone (10 mg/kg) enhanced ECG findings, improved the histopathological picture and downregulated apoptosis in cardiac tissues. Whereas the higher dose of pioglitazone (20 mg/kg) did not improve most of the measured parameters but rather worsened some of them, such as proapoptotic markers. Importantly, a positive correlation was found between serum AGEs and cardiac AGE receptors (RAGEs) versus caspase 3 expression in the two experiments. Therefore, the current effect of pioglitazone was, at least in part, mediated through downregulation of AGE-RAGE axis and inhibition of apoptosis. Consequently, these data suggest that pioglitazone, at optimized doses, may have utility in protection from acute MI.

A Case Series of Clenbuterol Toxicity Caused by Adulterated Heroin.

BACKGROUND: Adulteration of drugs of abuse may be done to increase profits. Some adulterants are relatively innocuous and others result in significant toxicity. Clenbuterol is a ß2-adrenergic agonist with veterinary uses that has not been approved by the U.S. Food and Drug Administration for human use. It is an infrequently reported heroin adulterant. We describe a cluster of hospitalized patients with laboratory-confirmed clenbuterol exposure resulting in serious clinical effects. CASE SERIES: Ten patients presented with unexpected symptoms shortly after heroin use. Seven evaluated by our medical toxicology service are summarized. Presenting symptoms included chest pain, dyspnea, palpitations, and nausea/vomiting. All patients were male, with a median age of 40 years (interquartile range [IQR] 38-46 years). Initial vital signs included a heart rate of 120 beats/min (IQR 91-137 beats/min), a respiratory rate of 20 breaths/min (IQR 18-22 breaths/min), a temperature of 36.8°C (IQR 36.7-37.0°C), a systolic blood pressure of 107 mm Hg (IQR 91-131 mm Hg), and a diastolic blood pressure of 49 mm Hg (IQR 40-70 mm Hg). Serum potassium nadir was 2.5 mEq/L (IQR 2.2-2.6 mEq/L), initial glucose was 179 mg/dL (IQR 125-231 mg/dL), initial lactate was 9.4 mmol/L (IQR 4.7-10.5 mmol/L), and peak creatine phosphokinase was 953 units/L (IQR 367-10,363 units/L). The median peak troponin level in six patients was 0.7 ng/mL (IQR 0.3-2.4 ng/mL). Three patients underwent cardiac catheterization and none had significant coronary artery disease. Clenbuterol was detected in all patients after comprehensive testing. All patients survived with supportive care. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Atypical presentations of illicit drug intoxication may raise concern for drug adulteration. In the case of heroin use, the presence of adrenergic symptoms or chest pain with hypokalemia, lactic acidosis, and hyperglycemia suggests adulteration with a ß-agonist, such as clenbuterol, and patients presenting with these symptoms often require hospitalization.

Clenbuterol toxicity: a NSW poisons information centre experience.

OBJECTIVE: To describe the epidemiology and toxicity of clenbuterol in exposures reported to the NSW Poisons Information Centre (NSWPIC). DESIGN AND SETTING: Retrospective observational study analysing data from all calls about clenbuterol exposure recorded in the NSWPIC database from 1 January 2004 to 31 December 2012. The NSWPIC coversthe Australian jurisdictions New South Wales, Tasmania and the Australian Capital Territory 24 hours a day and provides after-hours cover for the rest of Australia for 7 nights each fortnight. MAIN OUTCOME MEASURES: Total number of exposures, source of call (hospital, health care worker, member of the public), time from exposure to call, reasons for drug use, clinical features and advice given. RESULTS: Callers reported 63 exposures to clenbuterol, with a dramatic increase from three in 2008 to 27 in 2012. Of the 63 calls, 35 were from hospital, two from paramedics, one from general practice and 21 direct from the public. At least 53 patients (84%) required hospitalisation. The commonest reasons for use were bodybuilding and slimming. The most common features were tachycardia (24 patients), gastrointestinal disturbance (16) and tremor (11). Exposure was also associated with cardiotoxicity including one cardiac arrest in a 21-year-old man. CONCLUSION: Although a well recognised doping issue among elite athletes, clenbuterol use has spread out into the general public, especially during 2012, and should be considered in patients using bodybuilding or slimming products who present with protracted sympathomimetic features. The potential for misuse of this substance requires reconsideration of its current poison schedule registration and its availability.

Late diagnosis of an outbreak of leanness-enhancing agent-related food poisoning.

INTRODUCTION: Ractopamine is a leanness-enhancing agent approved in the United States and 26 other countries to reduce body fat content, increase muscle mass, and improve growth rate of certain food-producing animals. Other ß-agonists with stronger pharmacologic effects, especially clenbuterol, had been illegally used as leanness-enhancing agents in the United States, China, and the European Union, and foodborne poisonings related to clenbuterol residue in meat or liver were rarely reported in the European Union and China. We describe an unusual outbreak of leanness-enhancing agent-related food poisoning in Taiwan and its associated diagnostic challenge. REPORT OF THE OUTBREAK: Twelve patients presented to the emergency department of a regional hospital after having dinner together. Their clinical manifestations included nausea, vomiting, palpitation, facial flush, trunk or limb numbness, tremor, headache, weakness, chill, and dyspnea. Laboratory workup revealed the presence of hypokalemia, leukocytosis, and hyperglycemia. Poisoning attributable to ß-agonists was suspected; however, the diagnosis of leanness-enhancing agent poisoning was delayed because there was no leftover meat for analysis and because the veterinary medicine was illegal in Taiwan. Clenbuterol and salbutamol were eventually detected in 10 patients' urine sample by using liquid chromatography-tandem mass spectrometry, and the concentrations ranged from 54 to 806 µg/L and from 0 to 4052 µg/L, respectively. CONCLUSION: ß-Agonist leanness-enhancing agent-related food poisonings are rarely encountered, especially in those countries where relevant veterinary medicines are banned, and may thus pose diagnostic challenge to both emergency physicians and clinical toxicologists.

A descriptive study of adverse events from clenbuterol misuse and abuse for weight loss and bodybuilding.

BACKGROUND: Clenbuterol is a ß2-agonist approved in the United States for veterinary use in nonfood animals. Clenbuterol use is emerging among bodybuilders and fitness enthusiasts attracted to the hypertrophic and lipolytic effects. CASES: This was a retrospective chart review of clenbuterol exposures reported to 2 poison control centers. Misuse of clenbuterol for weight loss and bodybuilding was reported in 11 of 13 clenbuterol users. Reported clinical effects included tachycardia, widened pulse pressure, tachypnea, hypokalemia, hyperglycemia, ST changes on electrocardiogram (ECG), elevated troponin, elevated creatine phosphokinase (CPK), palpitations, chest pain, and tremor. Measured serum clenbuterol concentration was 2983 pg/mL post 4.5 mg ingestion. Co-ingestants included T3 and anabolic steroids. Treatments included activated charcoal, benzodiazepines, ß-blockers, potassium replacement, and intravenous (IV) fluid. CONCLUSIONS: There is an increasing use of the Internet for illicit drug use for bodybuilding and weight loss purposes. These patients may not present as the stereotype of illicit drug abusers, but as healthy athletic low-risk patients. Clinical effects persisted greater than 24 hours with evidence of myocardial injury in 2 patients. Clenbuterol is increasingly being abused within the bodybuilding subculture. These cases illustrate the hidden dangers of clenbuterol abuse among bodybuilders and fitness enthusiasts.

[Clinical features and treatment of acute clenbuterol poisoning in children].

OBJECTIVE: To study clinical features, treatment and curative effects in children with acute clenbuterol poisoning, in order to provide a basis for early diagnosis and treatment. METHODS: Clinical data of 28 hospitalized children with acute clenbuterol poisoning in April 2011 were retrospectively studied. RESULTS: Of the 28 patients, there were 15 males and 13 females, aged 1 to 13 years (mean age 6.5±4.8 years). Vomiting, palpitations and limb shaking were found as main clinical manifestations in the patients. Main changes of blood biochemical included hypokalemia, lactic acidosis, hyperglycemia, hypsocreatinkinase. Snus tachycardia and S-T segment depression were observed on ECG. Patients' symptoms were gradually alleviated after 12-78 hours by use of beta blockers, potassium supplement, protecting the heart and other symptomatic and supportive treatment. Blood biochemical indexes were improved after 48 hours of admission. All of the patients were cured after 5 days. The symptoms of the patients do not longer occur during a follow up of half a month. CONCLUSIONS: Acute clenbuterol poisoning is characterized by vomiting, palpitations, limb shaking, hypokalemia, lactic acidosis and tachycardia in children. An early effective treatment of this disease can improve prognosis in children.

A descriptive study of an outbreak of clenbuterol-containing heroin.

STUDY OBJECTIVE: Illicit drugs may be adulterated with substances other than the sought-after substance of abuse. Although the true incidence and clinical effects of this practice are unknown, geographically disparate outbreaks of clinically significant adulteration continue to occur. We report on a recent outbreak of clenbuterol-adulterated heroin occurring along the East Coast of the United States. METHODS: After identification of index cases, 5 US poison centers collaborated with state and territorial health departments to alert the public of clenbuterol-tainted heroin. A case definition of clenbuterol-tainted heroin toxicity was promulgated, and emergency departments (EDs) were asked to contact poison centers when cases were identified. RESULTS: We identified 34 probable or confirmed ED presentations in 5 states during a 6-month period. Thirteen of the 34 patients met the criteria for "confirmed" exposures. Clenbuterol was identified in the blood and or urine of 12 of these 13 patients. Clenbuterol concentrations ranged from 2.4 to 26 ng/mL in the blood and 9.4 to 12,526 ng/mL in the urine. Symptoms included nausea, chest pain, palpitations, dyspnea, and tremor. Physical findings included significant tachycardia, hypotension, and laboratory evidence of hyperglycemia, hypokalemia, and increased lactate levels. Six patients demonstrated biochemical evidence of myocardial injury. Ten patients received beta-adrenergic antagonists without adverse effect. CONCLUSION: The adulteration of heroin by clenbuterol was associated with sympathomimetic effects, metabolic acidosis, and myocardial injury. The report also highlights how collaborative efforts among poison centers using the Centers for Disease Control and Prevention's Epi-X system rapidly identified a disease outbreak.

Case of low dose clenbuterol toxicity.

We present a case of acute clenbuterol toxicity following ingestion of 20 µg of clenbuterol, resulting in symptoms of sympathetic activation, sinus tachycardia and electrolyte derangement. The patient was managed conservatively with fluid resuscitation, electrolyte replacement and monitoring, and discharged following a 5-day stay in hospital.

Atypical reactions associated with heroin use--five states, January-April 2005.

Heroin use typically produces a well-recognized syndrome of euphoria, miosis, and respiratory and central nervous system depression; cardiovascular effects are not a common finding. In January 2005, a man aged 21 years in New Jersey was hospitalized with an atypical reaction (e.g., tachycardia and palpitations) after reported heroin use. During the next 3 months, 25 additional persons in five states were reported to poison control centers (PCCs) and local public health agencies with a similar reaction after reported heroin use; in all, 24 of 26 patients were hospitalized. Analysis of drug specimens or testing of urine was performed in certain cases; in eight patients, the veterinary pharmaceutical clenbuterol was detected. This report describes four representative cases and summarizes the investigation by state and local health and law enforcement authorities and CDC into the 26 cases of atypical reactions after heroin use reported in five states (Connecticut, New Jersey, New York, North Carolina, and South Carolina) during January 28-April 17, 2005. Unintentional or intentional adulteration of illicit drugs such as cocaine or heroin is an additional potential hazard associated with their use.

beta-blocker ingestion: an evidence-based consensus guideline for out-of-hospital management.

In 2003, US poison centers were contacted regarding ingestion of beta-blockers by 15,350 patients including 3766 (25%) under 6 years of age; 7415 (48%) were evaluated in healthcare facilities and 33 died. An evidence-based expert consensus process was used to create this guideline. Relevant articles were abstracted by a trained physician researcher. The first draft of the guideline was created by the primary author. The entire panel discussed and refined the guideline before its distribution to secondary reviewers for comment. The panel then made changes in response to comments received. The objective of this guideline is to assist US poison center personnel in the appropriate out-of-hospital triage and management of patients with suspected ingestions of beta-blockers by describing the process by which a beta-blocker ingestion might be managed, identifying the key decision elements in managing cases of beta-blocker ingestion, providing clear and practical recommendations that reflect the current state of knowledge, and identifying needs for research. This guideline applies to ingestion of beta-blockers alone and is based on an assessment of current scientific and clinical information. The panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and health professionals providing care, considering all of the circumstances involved. Recommendations are in chronological order of likely clinical use; the grade of recommendation is in parentheses. 1) Patients with stated or suspected self-harm or who are the victims of a potentially malicious administration of beta-blocker should be referred to an emergency department immediately. In general, this should occur regardless of the dose reported (Grade D). 2) Patients without evidence of self-harm should have further evaluation, including determination of the precise dose ingested, history of other medical conditions, and the presence of co-ingestants. Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose (whichever is lower) warrants consideration of referral to an emergency department. Ingestion of any excess dose of any beta-blocker in combination with a calcium channel blocker or the ingestion of any excess dose by an individual with serious underlying cardiovascular disease also warrants referral to an emergency department (Grade C). 3) Do not induce emesis. Consider the oral administration of activated charcoal if it is available and no contraindications are present but do not delay transportation to administer charcoal (Grade A). 4) Asymptomatic patients who ingest more than the referral dose should be sent to an emergency department if the ingestion occurred within 6 hours of contacting the poison center for an immediate-release product other than sotalol, within 8 hours of contacting the poison center for a sustained-release product, and 12 hours if they took sotalol (Grade C). 5) Ambulance transportation is recommended for patients who are referred to emergency departments because of the potential for life-threatening complications of beta-blocker overdose. Provide usual supportive care en route to the hospital, including intravenous fluids for hypotension (Grade D). 6) Follow-up calls should be made to determine outcome at appropriate intervals for up to 12-24 hours based on the judgment of the poison center staff (Grade D). 7) Asymptomatic patients who are referred to healthcare facilities should be monitored for at least 6 hours after ingestion if they took an immediate-release preparation other than sotalol, 8 hours if they took a sustained-release preparation, and 12 hours if they took sotalol. Routine 24-hour admission of an asymptomatic patient who has unintentionally ingested a sustained-release preparation is not warranted (Grade D).

Myotoxic effects of clenbuterol in the rat heart and soleus muscle.

Myocyte-specific necrosis in the heart and soleus muscle of adult male Wistar rats was investigated in response to a single subcutaneous injection of the anabolic beta(2)-adrenergic receptor agonist clenbuterol. Necrosis was immunohistochemically detected by administration of a myosin antibody 1 h before the clenbuterol challenge and quantified by using image analysis. Clenbuterol-induced myocyte necrosis occurred against a background of zero damage in control muscles. In the heart, the clenbuterol-induced necrosis was not uniform, being more abundant in the left subendocardium and peaking 2.4 mm from the apex. After position (2.4 mm from the apex), dose (5 mg clenbuterol/kg), and sampling time (12 h) were optimized, maximum cardiomyocyte necrosis was found to be 1.0 +/- 0.2%. In response to the same parameters (i.e., 5 mg of clenbuterol and sampled at 12 h), skeletal myocyte necrosis was 4.4 +/- 0.8% in the soleus. These data show significant myocyte-specific necrosis in the heart and skeletal muscle of the rat. Such irreversible damage in the heart suggests that clenbuterol may be damaging to long-term health.

Clinical and pharmacological profile in a clenbuterol epidemic poisoning of contaminated beef meat in Italy.

Long-acting beta adrenergic agonists, such as clenbuterol accumulate in the liver, but not meat of treated farm animals, and result in epidemic poisonings in consumers. We describe an outbreak of poisoning in 15 people, following the consumption of meat. Clinical symptoms (distal tremors, palpitations, headache, tachipnoea-dyspnoea, and also moderate hyperglycaemia, hypokalemia and leucocytosis) were seen in nine hospitalised patients, starting about 0.5-3 h after poisoning, and disappearing within 3-5 days later. Clenbuterol was found in the urine of all the symptomatic patients, at higher levels than pharmacokinetic computing (mean level 28 ng/ml, 36 h after ingestion), based on the levels found in the meat (1140-1480 ng/g edible tissue). Thus, epidemic poisoning can be produced following the consumption of contaminated meat. The need for a better definition of pharmaco- and toxico-kinetics, not only for drugs ingested as parent drug, but also when ingested as residues with animal tissues, is recommended.

Concepts and controversies of bronchodilator overdose.

Beta-adrenergic agonists and theophylline are both capable of producing tremor, agitation, tachycardia, metabolic acidosis, hypokalemia, hyperglycemia, cardiac arrhythmias, and seizures. However, theophylline preparations, especially in the sustained-release formulations, are associated with a much higher incidence of morbidity and mortality secondary to status epilepticus and cardiovascular collapse. Overdoses of sustained-release preparations place patients at exceedingly high risk. This article describes the differentiation of the patient with acute and chronic theophylline overdoses and the implications for management of both clinical states.

Validation of ELISA test kits for detection of beta-agonist residues in meat.

Three ELISA test kits, the Randox ELISA beta-agonist test kit, Euro-Diagnostica test kit, and Ridascreen beta-agonist test kit, were evaluated for screening of meat and liver for beta-agonist residues in fortified and field-incurred samples. It was found that the Randox beta-agonist test kit was more suitable as a screening tool due to its accuracy, ease of use, and lower cost. The tests were able to detect beta-agonist residues at the minimum level of detection, as claimed by the suppliers. The performance of the method as assessed through recovery rates of beta-agonists in fortified samples was satisfactory with a low coefficient of variation (1-3%). Repeatability, as measured through the coefficient of correlation was also satisfactory. For field-incurred positive samples, the test kit showed a sensitivity of 100% and a low rate of false positives for goat and cow tissues. However, a high rate of apparent false positives was obtained for tissues of swine.

[Toxicological effects of clenbuterol in human and animals].

It is reported that clenbuterol increases the lean- to fat conversion in livestock and is an illegal stimulating and growth promoter. Consumption of meat containing clenbuterol residues causes adverse health effects in human, reduces the performance in exercise and disturbs reproductive system and hormone response. The toxicity of clenbuterol and its mechanism is reviewed in this paper.

[Salbutamol intoxication].

A 20-year-old asthmatic woman who ingested 300 mg of salbutamol (Albuterol) and 30 g of paracetamol is presented. She had sinus tachycardia up to 160/min, hypotension (80/50 mmHg), tremor, hypokalemia (2.1 mEq/l) and hyperglycemia (12.1 mEq/l). Treatment was by gastric lavage, fluids, potassium and N-acetylcysteine. Symptoms resolved in 24 hours.

Acute poisoning with clenbuterol--a case report.

In the paper we have described a case of acute, unintentional intoxication with clenbuterol, a selective beta 2-agonist. A 21-year-old bodybuilder to improve his physical fitness and to increase his muscle bulk was using clenbuterol in a dose of two tablets (20 mg) daily for a week before poisoning. On a day of acute intoxication he drank orange juice containing 48 tablets (4.8 g) of clenbuterol, which had been placed there by his friends. The patient was admitted to our clinic with tachycardia at rate 160 bpm, headache, dizziness, tremor, sweats, muscle weakness, agitation. Serum potassium concentration was 2.6 mmol/L, blood glucose level 18.7 mmol/L. All the symptoms and biochemical abnormalities disappeared after intravenous treatment with propranolol (1.0 mg) and potassium chloride (60 mmol) within five hour period. This case indicates that more attention should be paid to clenbuterol widely used as a stimulant by athletes, especially by bodybuilders.

Toxin-induced cardiovascular failure.

Adverse cardiovascular events comprise a large portion of the morbidity and mortality in drug overdose emergencies. Adverse cardiovascular events encountered by emergency physicians treating poisoned patients include myocardial injury, hemodynamic compromise with shock, tachydysrhythmias, and cardiac arrest. Early signs of toxin-induced cardiovascular failure include bradycardia, tachycardia, and specific ECG findings. Treatment of toxicologic tachycardia relies on rapid supportive care along with proper use of benzodiazepines for sedation. Treatment of toxicologic bradycardia consists of the use of isotonic fluids, atropine, calcium salts, and glucagon. High-dose insulin euglycemia should be used early in the course of suspected severe poisoning and intravenous lipid emulsion given to patients who suffer cardiac arrest.