[Promethazine - an old pharmaceutical that has got a renaissance. An avalanche-like increase in the number of overdose cases in Sweden]. / Renässans för Lergigan med kraftig ökning av intoxikationsfall - Korrekt användning av fysostigmin vid överdosering medför minimal risk.

Promethazine is a phenothiazine derivative antihistamine first introduced in the 1940s that is used in multiple medical conditions as a sedative/hypnotic agent. The drug is not addictive, which probably explains why it is increasingly used in the care of drug addicts. During the recent decade the sales of promethazine in Sweden have increased threefold while the yearly number of overdose cases with this drug at the Swedish Poisons Centre has increased from 100 to nearly 700. The anticholinergic delirium that may be provoked by this poisoning carries a symptomatology which may resemble the symptoms seen after an intracranial catastrophe, wherefore some cases are exposed to unnecessary diagnostic measures and invasive ventilator treatment. The case report and literature review presented in this paper conclude that physostigmine is the drug of choice in delirium provoked by overdose of promethazine, and that its use in this setting carries a minimal risk of serious side effects.

A Danish Survey of Antihistamine Use and Poisoning Patterns.

The first-generation antihistamine, promethazine, became a prescription-only drug in Denmark as of December 2014. First-generation antihistamines are known to have a higher toxic potential than second-generation antihistamines. The aim of this study was to provide a nationwide description of the antihistamine use and poisoning pattern from 2007 to 2013 in Denmark based on two independent databases. There were 1049 antihistamine exposures in the national, advisory telephone service specialized in poisonings, the Danish Poison and Information Centre (DPIC), and 456 exposures in the three registers used within the State Serum Institute of Denmark (SSI), a department under the Danish Ministry of Health dealing with research-based health surveillance in Denmark. First-generation antihistamines constitute 61% and 73% of antihistamine registrations in DPIC and SSI, respectively. Antihistamine exposures increased by 7 exposures/10,000 enquiries per year in DPIC and six admissions per year in SSI - this increase is not significant due to a sudden decrease in 2012. Intentional exposures constituted 65% in DPIC of which 82% was due to suicide attempts, and 78% of the involved antihistamines were first-generation antihistamines. Accidental exposures constituted 33% of which 61% were due to play and 29% involved first-generation antihistamines. Single antihistamine exposures constituted 65% of DPIC exposures of which 98% involved only one brand of antihistamine. Multidrug exposures constituted 35% of DPIC exposures with equally distributed coingestants. Hospitalization was recommended in 78% of DPIC exposures. Admissions required only 1-day of treatment in 91% of the SSI exposures. One of the 14 identified deaths in the SSI study population was directly related to antihistamine poisoning. Results support the limited disclosure of promethazine in Denmark and illustrate a generation-specific pattern indicating a suspected replacement of promethazine with other first-generation antihistamines.

A pseudoencephalitis presentation of a pediatric non-intentional intoxication.

UNLABELLED: We report a case of a pseudo encephalitis presentation of pediatric intoxication - Case report - a 7 year-old girl was admitted to our pediatric emergency unit after she developed sudden agitation, visual and tactile hallucinations. She was febrile (38.3 °C). She had not experienced any recent head trauma, infection or toxic ingestion; she did not take any medication for ADD. Her physical exam revealed tachycardia, normal pupils, reflexes and normal plantar responses. Laboratory investigations (complete blood count, basic metabolic panel, plasma lactate level, ammonia level) produced normal results. Lumbar puncture and computed tomography of the brain were normal. A serum and urine drug screening (benzodiazepines, barbiturates, cocaine, cannabis, amphetamines, methadone, ethanol) was negative. An electroencephalogram, performed during an episode of hallucinations, was compatible with benzodiazepine intoxication. A larger toxic detection by liquid chromatography/diode array detector (LC-DAD) detected promethazine and its metabolites. Symptoms lasted 20 h and she finally said she drank syrup from an over-the-counter cough suppressant medication. Comments - Anticholinergic syndrome is not well recognized or evoked in children presenting hallucinations. Promethazine is still present in several over-the-counter medications, alone or in combination with acetaminophen, carbocisteine or opiates. CONCLUSION: Medications containing promethazine should not be prescribed in children. Such intoxication can mimic encephalitis.

Clinical characteristics of cough mixture abusers referred to three substance abuse clinics in Hong Kong: a retrospective study.

OBJECTIVES. Cough mixture is the third most commonly abused substance in patients attending the Prince of Wales Hospital Substance Abuse Clinic. The content of the local cough mixture is not well researched. Paranoid psychosis manifesting as persecutory delusions and derogatory hallucination, as well as mood symptoms, is common in these patients. The natural history and outcome of such psychoses associated with cough mixture abuse are not well known. This study aimed to address these questions. METHODS. This was a retrospective study of cough mixture abuse in Hong Kong. Case records of cough mixture abusers currently receiving treatment at the 3 substance abuse clinics at the Prince of Wales Hospital, Alice Ho Miu Ling Nethersole Hospital, and the North District Hospital were retrieved for data collection. The patients' demographic data, duration and intake pattern of cough mixture, and use of any other drugs were documented. The presenting psychopathology, first urine toxicology results, diagnosis, treatment, number of hospitalizations, and course of the illness were also recorded. RESULTS. A total of 63 patients with the diagnosis of cough mixture abuse were identified in the database; 89% were male. The mean +/- SD age of the patients was 34.4 +/- 6.2 years; 67% were single and 83% were unemployed. The mean +/- SD age of onset of cough mixture abuse was 20 +/- 5 years. Psychiatric symptoms developed a mean +/- SD of 7.6 +/- 6.0 years after onset of abuse. According to the ICD-10 Mental and Behavioural Disorders criteria, the top psychiatric diagnoses were substance-induced psychotic disorder (67%), schizophrenia (19%), depressive disorder (11%), and dysthymia (10%). The most common ingredients in the urine sample at first presentation were promethazine (75%), pseudoephedrine (67%), codeine (60%), ephedrine (57%), zopiclone (17%), and hydrocodone (16%). Additionally, 16% of patients were in the priority follow-up group. The mean +/- SD follow-up period was 6.2 +/- 7.1 years during which there were 3.2 +/- 3.7 episodes of hospitalizations, with a mean +/- SD length of stay in each admission of 25.0 +/- 40.9 days. CONCLUSIONS. Promethazine, ephedrine, pseudoephedrine, codeine, and hydrocodone are the most common ingredients of cough mixture abused in this locality. Psychotic disorders are the most frequent psychiatric diagnosis associated with cough mixture abuse.

A study of the risk of mental retardation among children of pregnant women who have attempted suicide by means of a drug overdose.

BACKGROUND: The aim of the study was to estimate the effect on the fetal development of high doses of prescription drugs taken as a suicide attempt during pregnancy. METHODS: Pregnant women were identified among self-poisoned females in the toxicological inpatient clinic in Budapest between 1960 and 1993. Congenital abnormalities, intrauterine development based on birth weight and post-conceptional age, mental retardation, cognitive-behavioral status were compared in exposed children born to mothers who had attempted suicide by means of a drug overdose during pregnancy with their siblings, born either before or after the affected pregnancy, as sib controls. RESULTS: Of a total of 1 044 pregnant women, 74 used the combination of amobarbital, glutethimide and promethazine (Tardyl®, one of the most popular drugs for treatment of insomnia in Hungary) for suicide attempt. Of these 74 women, 27 delivered live-born babies. The mean dose of Tardyl® used for suicide attempts was 24 times the usually prescribed clinical dose. The rate of congenital abnormalities and intrauterine retardation was not higher in exposed children than in their sib controls. However, of the 27 exposed children, eight (29.6%) were mentally retarded (X²1=79.7, p= Sig) while mental retardation did not occur among 46 sib controls. These exposed children were born to mothers who attempted suicide with Tardyl® between the 14th and 20th post-conceptional weeks. The components of Tardyl® used separately for a suicide attempt during pregnancy were not associated with a higher risk of mental retardation. Therefore the high doses of Tardyl® associated with the high risk for mental retardation may be due to the interaction of its three drug components. CONCLUSIONS: The findings of the study showed that the high doses of a drug containing three components may be associated with a significantly increased risk for mental retardation without any structural defects, whereas each of these three component drugs taken alone was not associated with this adverse effect.

An autopsy case of multiple psychotropic drug poisoning.

A fatal poisoning case involving etizolam, phenobarbital, promethazine and chlorpromazine is presented. Quantitative toxicological analysis showed that the concentrations of etizolam, phenobarbital, promethazine and chlorpromazine in the femoral blood were 86 ng/ml, 5082 microg/ml, 0.107 microg/ml and 0.144 microg/ml, respectively, and large amounts of drugs were also detected in the stomach contents. We conclude that the cause of death was due to the interaction of multiple psychotropic drugs.

Promethazine overdose: clinical effects, predicting delirium and the effect of charcoal.

OBJECTIVE: The aim of this study was to describe the clinical effects of promethazine in overdose and explore the relationship between delirium and possible predictor variables. METHODS: A case series of promethazine poisonings was identified from a prospective database of poisoning admissions to a regional toxicology service. Data were extracted including demographics, details of ingestion, clinical features including delirium, complications and medical outcomes. In addition to descriptive statistics, a fully Bayesian approach using logistic regression was undertaken to investigate the relationship between predictor variables and delirium. RESULTS: There were 199 patients with 237 presentations, including 57 patients with 78 promethazine alone overdoses. Of these 57 patients who ingested promethazine alone the median age was 22 years [interquartile range (IQR): 17-31] and 42 were female (74%). The median dose ingested was 625 mg (IQR: 350-1250 mg). Median length of stay was 19 h (IQR: 13-27 h), ten were admitted to the intensive care unit (ICU) and four were ventilated. Delirium occurred in 33 patients (42%), tachycardia (HR>100) occurred on 44 occasions (56%) and hypotension only twice. There were no seizures, dysrhythmias or deaths. Multivariate analysis of 215 presentations (in 181 patients) where dose of promethazine ingested was known demonstrated that dose, administration of charcoal within 2 h and co-ingestants predicted whether patients developed delirium. No relationship was shown for sex and age. A plot of probability that a patient will develop delirium vs. dose was constructed which showed the probability of delirium for 250 mg was 31%, 500 mg was 42% and for 1 g was 55% for promethazine alone overdoses. CONCLUSION: The main feature of promethazine toxicity is delirium, the probability of which can be predicted from the dose ingested. The administration of charcoal and the presence of co-ingestants appears to reduce the probability of delirium in a predictable manner.

A study of the potential teratogenic effect of large doses of promethazine used for a suicide attempt by 32 pregnant women.

In Hungary, promethazine, a phenothiazine antihistamine, is the second most frequently used drug during pregnancy. The purpose of this study was to examine the effects of very large doses of promethazine that were used for a suicide attempt during pregnancy on embryo-fetal development. Self-poisoned pregnant women were identified from patients of the Department of Toxicology Internal Medicine, Korányi Hospital, Budapest, who were admitted from the three million people of Budapest and surrounding region. The rate of congenital abnormalities, intrauterine development (based on pregnancy age at delivery and birth weight), and cognitive-behavioral status of exposed children born to mothers who attempted suicide with promethazine alone or in combination with other drugs during pregnancy was compared with their sib controls. In all, 89 of the 1044 women with self-poisoning during pregnancy between 1960 and 1993 used promethazine for a suicide attempt. Of these 89 women, 32 delivered newborn babies. The dose of promethazine taken by these women for self-poisoning ranged between 125 mg and 1750 mg (mean of 544 mg, i.e., 21.8 tablets). Of the 32 promethazine-exposed children, nine (28.1 %) were affected with congenital abnormalities. However, of 11 pregnant women who attempted suicide with promethazine between the 3rd and 12th postconceptional week, that is, the critical period for production of most major congenital abnormalities, only three were affected with defects, and the critical periods for producing these defects did not overlap with the time of the suicide attempt during pregnancy. Of 34 unexposed sibs, five (14.7%) had congenital abnormalities; the difference in the total rate of congenital abnormalities between the exposed children and their sib controls was not significant. There also was no difference in pregnancy age-specific birth weight between exposed children and their sibs. Mean intelligence quotient was not reduced, and the incidence of behavioral deviation was not increased in the exposed children. The findings of this study did not indicate teratogenic or fetotoxic (including neurotoxic) effects of large doses of promethazine in children born to mothers who self-poisoned during pregnancy, although the total rate of congenital abnormalities was very high. Our experience shows the feasibility and benefits of using the self-poisoning model in estimating human teratogenic/fetotoxic risks of exposure to drugs.

Endovascular cooling in a patient with neuroleptic malignant syndrome.

We report a case of severe neuroleptic malignant syndrome with hyperthermia, rhabdomyolysis and hepatic failure where we applied endovascular cooling in order to reverse hyperthermia. After rapid normalization of core temperature at 37.5 degrees C, the patient's condition improved and CK levels dropped. However, upon withdrawl of endovascular temperature control there was a relapse. This is the first case where endovascular cooling was applied successfully in neuroleptic malignant syndrome.

Prolonged anticholinergic delirium following antihistamine overdose.

OBJECTIVE: A case of anticholinergic delirium in a female adolescent is described, exploring the pharmacokinetic reasons for the prolonged time course and reviewing the management provided. CONCLUSION: A 14 year old female hospitalised for depression ingested large quantities of promethazine and cyproheptadine. A severe anticholinergic delirium ensued which resolved after six days, much longer than the expected duration. The likely cause of the prolonged delirium was the interaction of promethazine and fluvoxamine through the inhibition of the CYP2D6 enzyme. The patient's young age, the severity of the poisoning and the use of drugs with anticholinergic properties to manage the delirium may also have contributed. The delirium may have been reversed had a cholinesterase inhibitor been provided soon after the overdose.

Mixed drug intoxication involving zaleplon ("Sonata").

Zaleplon ("Sonata") is a pyrazolopyrimidine derivative approved for use in the United States for the treatment of insomnia. To date, there has been little data in the toxicological literature where zaleplon has been implicated as causing a fatal intoxication, either alone or in combination with other drugs. This report documents a case where zaleplon was identified in a suicide by multiple drug ingestion. The following zaleplon concentrations were found: heart blood 2.2mg/l; bile 8.6mg/l and urine 1.4mg/l. Zaleplon was also detected but not quantitated in the kidney and liver.

[Suicidal attempts with old (currently unused) drug]. / Zatrucie samobójcze lekiem z przeszlosci.

Suicidal attempt with old (currently unused) drug is described. The suicidal attempts are usually performed with the use of contemporary pharmacotherapeutics. In the report a case of suicidal attempt with old drug Tardyl is presented. Tardyl (Glutethimid) was prescribed to the patient and has been stored for 20 years. The patient was previously treated for depression and many suicidal attempts. In the course of intoxication: balance disturbances, psychomotor retardation, changes in consciousness with temporary excitation were observed. The concentration of glutethimid in the urine was 1.1 mg% and 0.5 mg% in the blood. Patient was treated according to the general rules of intensive care. After 4 days of therapy the patient improved and was transferred to psychiatric unit in Koscian.

Redistribution of basic drugs into cardiac blood from surrounding tissues during early-stages postmortem.

The objective of this study was to elucidate the mechanism(s) responsible for increases in the concentrations of basic drugs in cardiac blood of bodies in a supine position during early-stages postmortem. The concentrations of basic drugs in cardiac blood and other fluids and tissues of three individuals who had used one or more basic drugs were examined. The results were compared with those obtained in experiments using rabbits. In the first case, autopsy of whom was performed approximately 12 h after death, methamphetamine was detected and its concentrations were in the order: lung >> pulmonary venous blood > blood in the left cardiac chambers (left cardiac blood) >> pulmonary arterial blood > blood in the right cardiac chambers (right cardiac blood). In the second case, autopsy of whom was performed approximately 9 h after death, methamphetamine and morphine were detected and their concentrations in the left cardiac blood were roughly twice those in the right cardiac blood. The methamphetamine and morphine concentrations in the lung were 2 to 4 times higher than those in cardiac blood samples. In the third case, autopsy of whom was performed approximately 2.5 days after death, the pulmonary veins and arteries were filled with chicken fat clots. Toxicological examination revealed the presence of four basic drugs: methamphetamine, amitriptyline, nortriptyline and promethazine. Their concentrations in the lung were 5 to 300 times higher than those in cardiac blood, but postmortem increases in the concentrations of these drugs in the cardiac blood were not observed. In the animal experiments, rabbits were given 5 mg/kg methamphetamine intravenously or 20 mg/kg amitriptyline subcutaneously and sacrificed 20 min or 1 h later, respectively. The carcasses were left in a supine position at the ambient temperature for 6 h after or without ligation of the large vessels around the heart. For the groups with ligated vessels, the mean ratios of the drug concentrations in both left and right cardiac blood samples 6 to 0 h postmortem were about 1, whereas in those without ligated vessels, these ratios were about 2 and 1, respectively. The order of the methamphetamine and amitriptyline concentrations in blood and tissue samples were roughly: lungs > myocardium and pulmonary venous blood > cardiac blood, inferior vena caval blood and liver. Our results demonstrate that when bodies are in a supine position, (1) basic drugs in the lungs diffuse rapidly postmortem into the left cardiac chambers via the pulmonary venous blood rather than simply diffusing across concentration gradients, and (2) basic drugs in the myocardium contribute little to the increases in their concentrations in cardiac blood during the early postmortem period.

Promethazine overdose: is it a "Goodnight" after all?

AIMS: To evaluate and describe the perceived increase in number of promethazine overdoses presenting to Auckland Hospital Emergency Department since Goodnight became available in New Zealand. METHOD: Emergency Department records were reviewed for 19.5 months from 19 December 1994 (when Goodnight became available on the New Zealand market) until 31 July 1996. The Emergency Department database for the preceding years dating back to 1 January 1984 was reviewed. RESULTS: There were a total of 25 patients (18 female; 7 male) with 17 patients being between the ages of 15-25. The first cases presented in April 1995 and 15 cases (60%) presented during the 1996 period of the study. Fifteen patients (60%) ingested one or more full boxes of Goodnight. Twelve patients (48%) were admitted to intensive care, eight of whom were intubated. Fifteen patients were discharged from hospital in under 24 hours, but five (20%) stayed 2-3 days. Records dating back to 1 January 1984 revealed a total of 31 cases of promethazine overdose in just under 11 years, nine being accidental ingestion in children less than 5 years of age. CONCLUSIONS: This review highlights the high morbidity and cost of having promethazine available as an unrestricted, pharmacy--only medication. It suggests that marketing laws should be reviewed and the availability of promethazine be curtailed.

Site-to-site variability of drug concentrations in skeletal muscle.

The homogeneity of drug concentrations in skeletal muscle was assessed in eight fatal overdoses. Ten to 30 random samples were taken from leg muscle weighing 1,650 to 7,985 g. For cases involving paracetamol the mean muscle-to-blood ratio ranged from 0.1 to 1.1 (n = 4) for amitriptyline 1.1 to 3.6 (n = 3), and for dothiepin 0.8 to 2.1 (n = 2). The coefficient of variance was large for all drugs, ranging from 10.5 (carbamazepine) to 50 (thioridazine). Skeletal muscle is not homogeneous with respect to drug concentrations in fatal overdose cases. Of 16 instances of drug detection in blood 2 (nortriptyline and promethazine) were not detected in muscle. Muscle-to-blood drug ratios varied significantly among cases, possibly influenced by survival time after drug ingestion. Quantitative interpretations of muscle drug levels present significant difficulties. However, skeletal muscle can be used for qualitative corroboration of blood analyses and is a suitable specimen for drug detection where none other is available.

Promethazine toxicity in a seven-month-old Doberman pinscher.

A 7-mo-old female Doberman Pinscher undergoing antibiotic treatment for tonsillitis was presented in near collapse with markedly low blood pressure, tachycardia, dilatation of pupils (non-responsive to light), and gastrointestinal distress. Since the owner could provide no history of significant toxin exposure, general supportive and non-specific toxicologic treatment protocols were initiated. Within 4 h marked improvement was observed. The owner's wife revealed that promethazine suppositories had been administered at a toxic level to control the vomition accompanying the tonsillitis.

Response of a promethazine-induced coma to flumazenil.

We report the first case of a patient in a promethazine-induced coma responding to treatment with flumazenil. A literature search conducted to determine the mechanism behind the antagonism of this overdose showed that promethazine interacts with receptors in the central nervous system. Sedative effects may, in fact, be mediated through the benzodiazepine receptor. We concluded that flumazenil can antagonize the sedative effects of promethazine at these receptors to return the patient to a wakeful state.

Nyquil-associated liver injury.

Acetaminophen, a commonly used medication, is present in many over-the-counter remedies. In recent years, its potential to cause severe liver injury has been increasingly appreciated. Chronic abusers of alcohol may be particularly susceptible to hepatotoxicity from acetaminophen. We report two cases of unintentional liver injury associated with ingestion of Nyquil, a liquid cold remedy containing acetaminophen and 25% alcohol.