First case reports of intentional Imepitoin overdose in humans: A case of two patients

Abstract

We report two cases of acute imepitoin overdose, a partial GABA-A receptor agonist. The first case involved a caucasian women of 22-year-old patient who ingested 20-24 g of imepitoin in a suicide attempt, presenting with central nervous system depression and mydriasis. The second case involved a caucasian male of 31-year-old patient who ingested 6–8 g of imepitoin along with other psychiatric medication, paracetamol, and ibuprofen. This patient presented with somnolence and bradylalia. Both patients received supportive care, including airway protection, intravenous fluids, activated charcoal, and cardiac monitoring. In the second case, flumazenil was administered and later discontinued. Both patients recovered fully within hours without complications. Imepitoin acts at the benzodiazepine binding site of the GABA-A receptor, approved for canine epilepsy and scarcely studied in humans, producing anxiolytic and anticonvulsant effects with reduced risk of sedation, dependence, or tolerance. It has a rapid absorption profile (T_max 0.5–2 h) and a variable half-life, shorter in smokers due to CYP1A2 induction.

Graphical Abstract

Highlights

• •To our knowledge, these are the first reported cases of imepitoin intoxication in humans.
• •Imepitoin is a partial GABA-A agonist, with anxiolytic and anticonvulsant effects and less sedation than benzodiazepines
• •Given its similarity to benzodiazepines, acute imepitoin intoxication management may resemble to benzodiazepine overdose.
• •The use of flumazenil should be individualized, as its risks like seizures and arrhythmias may outweigh the potential benefits.

1. Introduction

Imepitoin is a drug used in veterinary medicine, specifically indicated for idiopathic epilepsy, anxiety, and phobias in canines. This drug is not used in clinical medicine to treat similar conditions in humans. Therefore, there is limited information available in the human population. Imepitoin acts as a modulator of GABA receptors in the central nervous system (CNS) [1], [2], [3]. Structurally, this drug is classified as an imidazoline, a chemical class related to benzodiazepines. Its use in humans has been scarcely studied, as research was discontinued during the early phases of development because of pharmacokinetic differences between smokers and non-smokers, even though the compound demonstrated a favorable tolerability profile [4]. In this publication, we present two cases of imepitoin overdose and a review of the pharmacological characteristics of imepitoin, along with a proposed therapeutic approach to the management imepitoin intoxication. To our knowledge, these are the first reported cases of imepitoin intoxication in humans.

This case report was prepared following the CARE Guidelines [5].

2. Cases presentation

2.1. Case 1

We present a case of a 22-year-old Caucasian female with a psychiatric history of personality disorder and inconsistent medical follow-up. The patient had been prescribed aripiprazole, although treatment adherence was suboptimal.

She was brought to the emergency department (ED) by prehospital emergency services following an intentional overdose of approximately 50–60 tablets of imepitoin 400 milligrams (mg) (amounting to 20–24 g. The patient acknowledged suicidal intent behind the overdose. She had access to imepitoin because it was prescribed for her dog, who had been diagnosed with epilepsy.

On arrival at ED, paramedics had already performed nasogastric lavage and administered 50 g of activated charcoal. Upon presentation to the ED—approximately 90 min after ingestion—her only symptom was somnolence. On physical examination, vital signs were within normal limits (blood pressure 99/56 mmHg, heart rate 73 bpm, oxygen saturation 95 %), with a Glasgow Coma Scale (GCS) score of 13. Additional findings included bradylalia, dysarthria, and mydriatic pupils without associated nystagmus. Other higher cognitive functions were preserved.

Venous blood gas analysis showed a normal pH (7.359) with decreased pCO₂ and bicarbonate levels (38.8 mmHg and 21.9 mEq/L, respectively). Renal function and electrolyte levels were within normal limits, and the anion gap was 12.1 mEq/L. Calculated serum osmolality was also normal. Liver function tests, complete blood count, and coagulation parameters were all within normal reference ranges. Qualitative urine drug screening and blood ethanol levels were negative. Determination of imepitoin plasma concentrations was not conducted

In the ED, non-specific supportive treatment with intravenous fluids and oxygen therapy was initiated. After 16 h of clinical observation, the patient progressively regained full consciousness, reaching a GCS score of 15. Repeat blood tests at 9 h post-ingestion showed no significant abnormalities. The electrocardiogram (ECG) revealed a prolonged PR interval of 239 ms and a QTc interval of 473 ms.

Before medical discharge, the patient was evaluated by the psychiatry department, which concluded that she did not present a high risk of recurrent suicidal behavior.

2.2. Case 2

A 31-year-old Caucasian male with a psychiatric history of mixed anxiety–depressive disorder and personality disorder was admitted to the ED following an intentional drug overdose. The ingestion included 15–20 tablets of imepitoin 400 mg (6–8 g), 10 tablets of sertraline 100 mg (1 g), 10 tablets of bupropion 150 mg and 10 tablets of bupropion 300 mg (total of 4.5 g), 5 tablets of clorazepate 10 mg (50 mg), 10 tablets of paracetamol 1 g (10 g), and 20 tablets of ibuprofen 600 mg (12 g). The patient was transported by prehospital emergency services. He also confirmed suicidal intent behind the overdose. In this case, imepitoin was also available at the patient’s home as it had been prescribed for his dog with epilepsy.

Upon arrival at the patient’s residence, paramedics found him with normal vital signs and a GCS score of 15, though he tended to somnolence and bradylalia. At that point, 50 g of activated charcoal was administered, along with intravenous infusions of flumazenil and N-acetylcysteine.

At ED arrival, the patient remained hemodynamically stable (blood pressure: 123/72 mmHg, heart rate: 81 bpm, oxygen saturation: 98 %) and continued to present a GCS score of 15. Blood tests showed a normal complete blood count, venous blood gas with a pH of 7.322, pCO₂ of 51 mmHg, bicarbonate of 26.6 mEq/L, and lactate of 2.9 mmol/L. Renal function and electrolyte levels were preserved. The anion gap was 15.4 mEq/L. Liver function and coagulation parameters were within normal limits. Paracetamol levels measured at 4 h post-ingestion were < 2.0 µg/mL. A qualitative urine drug screen was positive only for benzodiazepines. Blood ethanol levels were negative. Electrocardiography showed no significant abnormalities, with a QTc interval of 456 ms. Imepitoin plasma levels were not assessed.

Twenty minutes after arrival at the ED, the flumazenil infusion was discontinued due to the patient’s maintained level of consciousness. N-acetylcysteine infusion was continued until two subsequent paracetamol levels (7 and 11 h after ingestion) remained below < 2.0 µg/mL.

After 14 h of clinical observation, the patient was evaluated by the psychiatry department, which determined that inpatient psychiatric hospitalization was necessary. The total length of stay was 20 days.

3. Discussion

To our knowledge, these are the first two reported cases of imepitoin intoxication in humans. Given the limited information available in humans, these reports provide valuable clinical insight into its manifestations and management. Both patients presented with relatively mild neurological symptoms without life-threatening complications and had a favorable outcome following conservative treatment. Another strength lies in the fact that both cases were managed conservatively, and the outcome was favorable, supporting the initial effectiveness of supportive care in this context. Furthermore, another relevant strength is that, in one of the cases, flumazenil was used safely without complications and seemed to be effective. This offers some practical insight into its possible role, although significant clinical uncertainty remains regarding its efficacy and safety in imepitoin overdose, since the patient also ingested clonazepam. This point is further discussed above.

Nevertheless, there are certain limitations, as these are case reports. Plasma levels of imepitoin were not determined, limiting the ability to correlate ingested dose with clinical effect. In the second case, co-ingestion of several other central nervous system depressants complicates interpretation of the specific effects attributable to imepitoin. Furthermore, long-term outcomes following discharge are unknown.

Imepitoin belongs to the imidazoline family and functions as a low-affinity partial agonist at the GABA-A receptor in the CNS (12–21 % compared to diazepam) [4]. It is not linked to tolerance or dependence during long-term use, unlike classical benzodiazepines such as diazepam or clonazepam [4], [6].

The pharmacodynamic activity has been demonstrated in seizure and genetic models of epilepsy in rats and mice [4]. Furthermore, imepitoin has also shown a weak calcium channel blocking effect, which may contribute to its anticonvulsive properties [1]. In-vitro studies have shown that flumazenil can reverse GABA-A receptor occupancy induced by imepitoin, although clinical evidence is lacking [7]. This may correlate with the second case presented, where the patient supposedly responded to flumazenil, however, the effect of flumazenil cannot be isolated, as the patient had co-ingested multiple central nervous system depressants, including benzodiazepines, making it uncertain whether flumazenil administration had a real impact on the clinical course of the imepitoin intoxication.

Preclinical data in rats and mice showed that single oral doses over 2.150 mg/kg did not induce lethality (LD₅₀), and repeated-dose toxicity studies of the highest tested oral dose (316 mg/kg) resulted solely in non-specific and reversible toxic effects [4]. In beagle dogs, imepitoin reaches peak plasma concentrations within 2–3 h, has moderate protein binding (60–70 %), high volume of distribution (579–1548 mL/kg), and a short half-life (1.5–2 h), with metabolism occurring via hepatic oxidative pathways [1], [4]. Co-administration with food reduced the AUC by 30 %, without a significant change in T_max and C_max values [1], [4].

Phase I studies in humans indicated that single doses of up to 800 mg per day and repeated 500 mg every 12 h were well tolerated [4]. Adverse effects included headache, dizziness, and fatigue, with QT interval prolongation observed primarily in non-smokers [4]. A rapid absorption profile was observed, showing a T_max between 0.5 and 2 h, and a considerably variable elimination half-life depending on the administered dose, treatment duration, and smoking status, approximately 8 h in non-smokers and 3.96 h in smokers, likely due to CYP1A2 induction [4].

Given the pharmacodynamic similarities to benzodiazepines and the lack of specific evidence, we extrapolated that acute imepitoin intoxication may be managed similarly to benzodiazepine overdose. Supportive care is the mainstay of treatment, and priority should be given to securing the airway, ensuring adequate ventilation, and maintaining hemodynamic stability [8]. Electrocardiography and continuous telemetry are recommended in patients presenting with signs of acute intoxication, due to the risk of malignant arrhythmias and QT interval prolongation potentially associated with imepitoin [4], particularly in patients concurrently taking other QT-prolonging drugs (such as antipsychotics), as was the case in both patients reported. Although activated charcoal is known to adsorb benzodiazepines [10], its routine use in cases of isolated benzodiazepine intoxication remains controversial due to the lack of consistent evidence demonstrating a clear clinical benefit [8]. To date, the adsorption of imepitoin by activated charcoal has not been investigated.

Although flumazenil demonstrated apparent clinical benefit in one patient and has shown efficacy in reversing imepitoin's effects in vitro, we do not recommend its routine use, since it may increase the risk of cardiac arrhythmias [8], [9], [10] and further exacerbate QT interval prolongation associated with imepitoin [4]. Additionally, its use is contraindicated in patients with a history of epilepsy, due to the risk of seizure induction, and in those on chronic benzodiazepine therapy, where it may precipitate acute withdrawal syndrome [8], [9], [10]. Flumazenil administration should be reserved for carefully selected patients, after a thorough, individualized assessment of the benefit–risk balance, and only when the clinical scenario justifies it.

4. Conclusion

These two cases represent the first reported cases of imepitoin overdose in humans and offer initial clinical insight into its presentation and management. Both patients experienced a relatively mild course characterized by transient neurological symptoms, with full recovery following supportive care and, in one of the cases, with the administration of flumazenil. Acute imepitoin overdose may clinically resemble benzodiazepine overdose due to its pharmacodynamic similarities, although its sedative potential is theoretically lower because of its partial agonism at the GABA-A receptor. Supportive care should be prioritized in the emergency setting, as it was sufficient in both cases presented and is likely adequate in acute imepitoin overdose. Electrocardiography and initiating continuous monitoring are advisable due to the potential for QT interval prolongation, especially in patients taking other QT-prolonging agents. The use of activated charcoal for gastrointestinal decontamination has not been specifically evaluated in imepitoin overdose and should be guided by current clinical practice guidelines. The use of flumazenil remains controversial, as it may carry greater risks than benefits in this context, and should not be routine; it may be considered only after individualized risk–benefit assessment.

CRediT authorship contribution statement

Gerard Ronda-Roca: Writing – original draft, Conceptualization. Antonio F Caballero-Bermejo: Writing – review & editing. Belén Ruiz-Antorán: Writing – review & editing, Supervision. José Cantillana-Barrenas: Writing – original draft.

Funding sources

This case report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data statement

Data used to prepare this case report is confidential data, since it includes sensitive or confidential information such as patient data.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Handling Editor: Dr. L.H. Lash

Data availability

The data that has been used is confidential.