Ilene B. Anderson

Pennyroyal toxicity: measurement of toxic metabolite levels in two cases and review of the literature.

An increasing segment of the U.S. population is seeking alternatives to traditional Western allopathic medicine. In 1990, Americans made an estimated 425 million visits to providers of unconventional therapies [1]. One particularly popular alternative is herbal medication. Herbal medicines are promoted as more natural and therefore safer than conventional over-the-counter and prescription medicines, but many may be more dangerous than conventional pharmaceutical agents [2]. Both over-the-counter and prescription medicines in the United States must be extensively tested and certified before the Food and Drug Administration approves them for indicated uses. In contrast, herbal preparations are not subjected to such scrutiny before being promoted and sold. Pennyroyal is one widely available herbal medicine that can be life threatening after ingestion. Pennyroyal, an herb consisting of the leaves of either Mentha pulegium or Hedeoma pulegioides, primarily contains pulegone (Figure 1) plus smaller amounts of several other monoterpenes that are encountered in mint species [3]. Pennyroyal is commonly available in health food stores. Since Roman times, herbalists have recommended the herb as an abortifacient [4]. Although no evidence supports its efficacy in this regard [5], many herbal books continue to cite the use of pennyroyal for this purpose [6, 7], despite reports of centrilobular hepatic necrosis and death in connection with its use [8-11]. Pennyroyal is also advocated as a pesticide, primarily for controlling fleas on domestic pets and in the home [12]. Hepatotoxicity and other cellular damage have been reported in a household pet treated with pennyroyal oil [13]. Figure 1. Structures of the major monoterpene in pennyroyal, (R)-(+)-pulegone, and its major proximate toxic metabolite, menthofuran. Pennyroyal poisoning continues to occur regularly. Although pennyroyal ingestion can be fatal, cases of poisoning have only been sporadically documented in the modern medical literature, and none has involved the use of recent analytic techniques to measure pennyroyal metabolite levels. We report four recent cases of pennyroyal toxicity, two of which had laboratory confirmation of pulegone or its major toxic metabolite menthofuran [14]. We also review all of the published clinical case data from earlier reports and place our four cases in the context of reported signs and symptoms of toxicity. Methods Quantification of Pulegone and Menthofuran Plasma samples were acidified and extracted with diethylether after internal standards were added. To identify and quantify pulegone and menthofuran [14, 15], we compared their gas chromatographic retention times and mass spectra with those of known standards. Gas chromatographic analysis was done on a Hewlett-Packard (Palo Alto, California) Model 5980. Chromatography was done on a 30 m 0.320 mm Wall Coated Open Tubular DB-5 fused silica capillary column (J & W Scientific, Folsom, California). Electron-impact mass spectrometry was done using a VG-7070H double-focusing instrument (Manchester, United Kingdom) that was equipped with a Hewlett-Packard Model 5980 Series II gas chromatograph and was electronically linked to a Mass Spectrometry Service data system (Manchester, United Kingdom). Identification of Protein-Bound Pennyroyal Metabolites by Western Blot Analysis Liver microsomes were prepared from a liver sample obtained from patient 1 and from a human liver sample obtained from the University of Washington School of Pharmacy Liver Bank. To provide a positive control, a portion of the latter sample was incubated with menthofuran and an NADPH (reduced nicotinamide adenine dinucleotide phosphate)-regenerating system. Microsomal proteins were subjected to electrophoresis in sodium dodecyl sulfate-polyacrylamide gels, and the protein bands were transferred to nitrocellulose solid support. Protein adducts were detected using a primary antibody obtained from rabbits immunized with chemically synthesized oxidative metabolites of menthofuran coupled to metallothionein and with a secondary antibody of horseradish peroxidase-conjugated goat antirabbit IgG (Pierce Chemical Co., Rockford, Illinois). The membranes were developed using 0.004% nickel chloride, 0.0075% hydrogen peroxide, and 0.05% 3,3-diaminobenzidine tetrahydrochloride. Poison Center Reporting We selected patients by reviewing all cases involving pennyroyal ingestion for which the San Francisco Bay Area Regional Poison Control Center was primarily consulted during a 2-year period. We included all medically treated or symptomatic cases and excluded two other cases initially reported to a collaborating regional poison control center for which our service provided a secondary consultation. All data were collected by telephone and were recorded on a standard American Association Poison Control Center Cooperative Poison Center report form at the time of the initial consultation. The poison information specialist obtained all pertinent information available. Follow-up contact by telephone was continued until the clinical outcome was determined. The San Francisco Poison Control Center receives an average of 60 000 consultations each year [16]. Literature Review We identified case reports by searching MEDLINE and Index Medicus and by reviewing the reference citations of all available publications. One reference citation was supposedly a case report of pennyroyal poisoning; however, we later reviewed the original report and discovered that the case did not involve poisoning and appears to have been cited in error [17]. Only 7 of the 18 cases are from the modern medical literature; the others were reported before 1905. The cases reported before 1905 are less well documented, but we did not exclude cases for this reason. Case Reports Case 1 A 24-year-old woman repeatedly ingested pennyroyal herbal extract (pennyroyal herb, 48% to 56% in an alcohol base) and black cohosh root (Cimicifuga racemosa) extract for 2 weeks in an attempt to induce an abortion. When this was unsuccessful, she ingested additional unknown amounts of pennyroyal herbal extract and black cohosh root extract over a short period. Soon after, abdominal cramps, chills, vomiting, and syncope developed, and the patient had difficulty walking. She was placed in a cold bath 7 hours after the acute ingestion and began to manifest rigors that her roommate interpreted as a seizure. Paramedics found the patient in cardiopulmonary arrest at a time estimated to be 7.5 hours after the acute ingestion. The patient was intubated, and then cardiopulmonary resuscitation was initiated and continued for 22 minutes until the patient arrived at the hospital. On arrival at the emergency department, the patients heart rate was 120 beats/min and her blood pressure was 70/40 mm Hg while she received maximal dopamine. Her pupils were fixed and dilated. The physical examination showed coma and a rigid abdomen. A computed tomographic scan of the abdomen suggested a possible ruptured ectopic pregnancy. Initial laboratory values were the following: sodium level, 157 mmol/L; potassium level, 5.7 mmol/L; chlorine level, 107 mmol/L; bicarbonate level, 8 mmol/L; blood urea nitrogen level, 5.0 mmol/L; creatinine level, 221 mol/L; glucose level, 6.8 mmol/L; lactic acid level, 21.0 mmol/L; leukocyte count, 37.3 109/L; hemoglobin level, 89 g/L; hematocrit, 0.28; platelet count, 256 109/L; albumin level, 27 g/L; total bilirubin level, 5.1 mol/L; aspartate aminotransferase level, 0.82 kat/L; lactate dehydrogenase level, 3.54 kat/L; amylase level, 2.35 kat/L; prothrombin time, 23 seconds; partial prothrombin time, 68 seconds; and international normalized ratio, 4.1. A quantitative plasma human chorionic gonadotropin level indicated that the patient was 1 to 3 months pregnant. Arterial blood gas values (measured while the patient received 100% O2 by endotracheal tube) were the following: pH, 6.61; Pco 2, 23 mm Hg; and Po 2, 503 mm Hg. A toxicology screen was negative for alcohol, acetaminophen, and salicylates. Laboratory values 36 hours after the acute ingestion were notable for the aspartate aminotransferase level (44.53 kat/L), the alanine aminotransferase level (29.12 kat/L), and the lactate dehydrogenase level (68.18 kat/L). Throughout the initial 12 hours of hospitalization, the patients course was marked by hemodynamic shock, decreasing hematocrit, and a clinical picture consistent with disseminated intravascular coagulation. During hospitalization, the patient received 10 units of packed red blood cells and multiple units of fresh frozen plasma. Exploratory laparotomy showed a hemorrhagic, right-sided ectopic pregnancy with indications of superinfection. A substantial amount of old blood, not otherwise quantified, was found. The pregnancy was not ruptured, but there was evidence of bleeding from the end of the tube. No active bleeding was seen during surgery. A computed tomographic scan of the head was consistent with anoxic encephalopathy. The patient remained unresponsive to all stimuli. Life support was withdrawn, and the patient died 46 hours after the acute pennyroyal ingestion. Other than the anticipated brain and uterine findings, the most notable abnormalities at autopsy were found in the liver. The substantial centrilobular degeneration and necrosis of the hepatic cells were consistent with a specific toxic insult. Diffuse degenerative changes involving the proximal tubules of the kidney were also noted. The pathologist concluded that the cause of death was multiorgan failure and anoxic encephalopathy secondary to ingestion of pennyroyal and black cohosh. Blood from the heart, collected at autopsy 26 hours after death, was tested for the presence of pulegone and menthofuran. The pennyroyal and black cohosh herbal extracts that the patient had ingested were also tested for the presence of pulegone and menthofuran (Table 1). Table 1. Laboratory Values of Pennyroyal Metabolites in Case 1* Po

Shorter duration of oral N -Acetylcysteine therapy for acute acetaminophen overdose

STUDY OBJECTIVE We sought to evaluate the safety and efficacy of a shorter N -acetylcysteine (NAC) regimen in the treatment of acute acetaminophen overdose. METHODS We performed a retrospective case series in a large urban county hospital. Of 305 patients identified through the emergency department, 75 patients met the criteria inclusion: an acute overdose ingestion, serum acetaminophen concentration in toxic range according to the Rumack-Matthew nomogram, and oral NAC treatment initiated within 24 hours of the ingestion. The regional poison control center recommended oral treatment with NAC 140 mg/kg, followed by maintenance doses of 70 mg/kg every 4 hours until the serum acetaminophen level was no longer detectable, rather than the standard 72-hour treatment regimen. RESULTS The primary outcome measure was the development of hepatotoxicity. Twenty-five (33.3%) patients were treated for a period of less than 24 hours, 25 (33.3%) were treated for 24 to 36 hours, and 25 (33.3%) were treated for 37 to 64 hours; the mean and median duration of treatment was 31 hours. None of the patients treated for less than 24 hours had evidence of hepatotoxicity (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] level >1,000 IU/L); hepatotoxicity developed in 2 (8%) patients treated for 24 to 36 hours and 4 (16%) patients treated for 37 to 64 hours. There were no deaths or patients who received liver transplantation. The overall incidence of hepatotoxicity in our patients was similar to that found in other protocols with administration of oral NAC for 72 hours or intravenous NAC for 20 or 48 hours. CONCLUSION This observational study suggests that a shorter course of oral NAC therapy in patients who do not show evidence of hepatotoxicity within 36 hours of an acute acetaminophen overdose is safe and effective. [Woo OF, Mueller PD, Olson KR, Anderson IB, Kim SY. Shorter duration of oral N -acetylcysteine therapy for acute acetami-nophen overdose. Ann Emerg Med . April 2000;35:363-368.].

High-risk behaviors and hospitalizations among gamma hydroxybutyrate (GHB) users.

Introduction: Little is known about behaviors linked to gamma hydroxybutyrate (GHB) morbidity. Methods: We surveyed 131 GHB users, using logistic regression to test the associations between the high risk behaviors and hospital treatment for GHB (26 [20%] of subjects). Results: Increased risk of GHB hospital treatment was associated with: co-ingestion of ethanol (OR 5.2; 95% CI 1.7–16), driving under the influence of GHB (OR 3.2; 95%, CI 1.3–7.8),use of GHB to treat withdrawal symptoms (OR 2.9; 95% CI 1.1–7.9), and co-ingestion of ketamine (OR 2.7; 95% CI 1.1–6.7). Conclusion: Targeted prevention activities could focus on selected high-risk behaviors.

An Evaluation of Selected Herbal Reference Texts and Comparison to Published Reports of Adverse Herbal Events

ObjectiveThere has been a recent proliferation of medical reference texts intended to guide practitioners whose patients use herbal therapies. We systematically assessed six herbal reference texts to evaluate the information they contain on herbal toxicity.MethodsWe selected six major herbal references published from 1996 to 2000 to evaluate the adequacy of their toxicological information in light of published adverse events. To identify herbs most relevant to toxicology, we reviewed herbal-related calls to our regional California Poison Control System, San Francisco division (CPCS-SF) in 1998 and identified the 12 herbs (defined as botanical dietary supplements) most frequently involved in these CPCS-SF referrals. We searched Medline (1966 to 2000) to identify published reports of adverse effects potentially related to these same 12 herbs. We scored each herbal reference text on the basis of information inclusiveness for the target 12 herbs, with a maximal overall score of 3.ResultsThe herbs, identified on the basis of CPCS-SF call frequency were: St John’s wort, ma huang, echinacea, guarana, ginkgo, ginseng, valerian, tea tree oil, goldenseal, arnica, yohimbe and kava kava. The overall herbal reference scores ranged from 2.2 to 0.4 (median 1.1). The Natural Medicines Comprehensive Database received the highest overall score and was the most complete and useful reference source. All of the references, however, lacked sufficient information on management of herbal medicine overdose, and several had incorrect overdose management guidelines that could negatively impact patient care.ConclusionCurrent herbal reference texts do not contain sufficient information for the assessment and management of adverse health effects of botanical therapies.

Lamotrigine-induced seizures in a child: case report and literature review.

Introduction. Lamotrigine is an antiepileptic agent. There is only one previous report of a seizure associated with lamotrigine overdose with laboratory confirmation (a 2-year-old girl, lamotrigine level of 3.8 mg/L). Case Report. A healthy 19-month-old boy ingested an unknown amount of his sisters lamotrigine tablets. Twenty minutes later, the child experienced generalized seizure activity lasting 10 seconds, followed by another brief self-limited seizure. Vitals signs: heart rate 152–207 bpm crying, respiratory rate 26 /min, temperature 95.7°F, and pupils 3mm. The one-hour lamotrigine level = 20.3 mg/L. The child was discharged 24 hours later. Literature Review. Six previous case reports of lamotrigine poisoning with serum levels, as well as a retrospective review of lamotrigine exposures, are discussed. Conclusion. A case of lamotrigine-induced seizures in a pediatric patient is reported, with a level approximately five times the upper limit of the therapeutic range. The pediatric population may be at increased risk of seizures following lamotrigine poisoning, and serum levels may not be clinically useful for predicting outcome after overdose.

Influence of age on Salvia divinorum use: results of an Internet survey.

Abstract An Internet-based survey of Salvia divinorum (“salvia”) users was conducted to identify correlates surrounding its use. Salvia-knowledgeable persons were recruited via “social networking Internet websites” (n = 23) where notices were posted on recreational salvia group message boards (n = 69). Data collection included demographics, use circumstances, experiences, and age (current and at first salvia use). A total of 219 surveys were analyzed. Salvia users who were young adults (≤21yrs) at first use favored salvia for fun (OR = 1.94, CI = 1.08–3.49, p = 0.03) or to relieve boredom (OR = 2.06 CI = 1.09–3.91, p = 0.02), while salvia users who were adults (≥22yrs) at first use favored salvia for spiritual effects (OR = 2.63, CI = 1.02–6.75, p = 0.04). Being an adult at first use was associated with higher odds of concurrent marijuana (OR = 2.68, CI = 1.50–4.78, p = 0.0007) or tobacco use (OR = 1.94, CI = 1.05–3.60, p = 0.03). Over half of all respondents reported use reduction or cessation in the past 12 months (114 of 219, 52%), citing dishke of the high (33.3%) or loss of interest in salvia (28.9%). Reports of cessation suggest salvia use may be more attributed to curiosity than continual abuse.

Area-level socioeconomic status in relation to outcomes in γ-hydroxybutyrate intoxication

Background. Area-level socioeconomic status (SES) may play an important role in drug abuse patterns, including related health outcomes. This may be particularly relevant for γ-hydroxybutyrate (GHB), which is prototypical of “party” drug abuse. Methods. We retrospectively reviewed GHB-related cases reported to the California Poison Control System (CPCS; January 1, 1999 through June 30, 2007). We limited analysis to CPCS calls containing a residential zip code (ZC). The CPCS data were extracted for key case characteristics, including the residential ZC. We linked cases to corresponding 2000 U.S. Census data for area-level measures of SES and demographics. We used multiple logistic regression analysis to test the associations between area-level SES and GHB case severity, taking into account area-level demographics and individual-level GHB high-risk behaviors. Results. We analyzed 210 cases. Taking into account area-level demographics (age and racial mix; urbanicity) and GHB-related high-risk behaviors (use of GHB congeners; GHB-dependence; co-ingestion of other agents), we associated higher area-level SES with greater GHB case severity. There was 40% increased likelihood of major GHB adverse health outcomes for every 

Systematic Assessment of Gamma Hydroxybutyrate (GHB) Effects During and After Acute Intoxication

100,000 incremental increase in median home values (OR 1.41; 95% CI 1.1–1.8). For median annual household income (per 

Topical antacid therapy for capsaicin-induced dermal pain: a poison center telephone-directed study

10,000), the association was similar (OR 1.39; 95% CI 1.0–1.9). Conclusion. Higher area-level SES is associated with greater GHB-related case severity. This study may serve as a model using a geographic information system (GIS) approach to study the population-based correlates of drugs of abuse reported through poison control surveillance.

The impact of gamma hydroxybutyrate (GHB) legal restrictions on patterns of use: Results from an International Survey

We adapted and tested a previously published questionnaire battery eliciting sensory and cognitive symptoms during (acute) and immediately after (post-acute) GHB intoxication. Studying 125 GHB users, we assessed the instruments internal consistency using Cronbachs alpha (CA) and responsiveness to change comparing acute and post-acute symptoms. The final 14-item battery demonstrated good internal consistency (CA >or= 0.85, both acute and post-acute). The median symptom score (possible range 0-64) was 30 (acute) and 6 (post-acute; difference p < 0.001). This modified substance-specific symptom battery, which is easily administered, demonstrated excellent performance characteristics. It can be used to study GHB and, potentially, related drugs of abuse.