Introduction

Hedera helix (ivy leaf), one of the 15 species of the genus Hederae, is an evergreen ivy from the Araliaceae family. Ivys are found naturally in Asia, North America, Eastern, Central and Southern Europe. It is a common decorative plant. The biological active compund responsible for the medical use of Hedera helix are triterpene saponins. The saponins are naturally occurring surface-active glycosides. They are mainly produced by plants such as soyabean, yucca and English ivy but also by lower marine animals such as sea cucumber and starfish (¹,²). Of these saponins, 1.7-4.8 % is hederacoside C, 0.4-0.8 % is hederacoside D, 0.1-0.2 % is hederacoside B and 0.1-0.3 % is α-hederin. As a result of preclinical studies, it has been shown that ivy leaf extracts have bronchodilator, spasmolytic and antibacterial effects, especially α-hederin with secretolytic and bronchospasmolytic properties (³).

The fresh fruits and leaves of Hedera helix ivy are toxic and can cause gastrointestinal tract mucosa irritation, bloody diarrhea and even death (⁴). The well-known side effect is contact dermatitis and many cases have been reported (⁵,⁶,⁷). Hausen et al. (⁸) reported that ivy leaf is a strong irritant based on chemical, laboratory and clinical studies. Therefore, Hedera helix, which contains 10 % α and ß hederin saponins, is very irritant to mucosal surfaces (⁹).

Apart from the improper use of drugs resulting from therapeutic errors, drug intoxications in adult humans are often caused by misuse, abuse or conscious suicide. In children and animals, the cause of poisoning with over-the-counter drugs is often accidental ingestion and exposure to the drugs when they are not under supervision by a caretaker. Albeit many over-the-counter drugs are not highly toxic; affected animal’s age and size, the amount of the drug ingested, and the duration of the exposure play a role in severity of the poisoning symptoms (¹⁰).

Most commonly reported unprescribed medication toxicities are nonsteroidal anti-inflammatory drug poisoning such as aspirin poisoning, causing gastric irritation because of enterohepatic recycling in cats and dogs; ibuprofen poisoning, causing nausea, vomiting, abdominal pain, gastrointestinal ulceration and mild central nervous system depression; naproxen poisoning; causing gastrointestinal signs along with renal insufficiency; acetaminophen poisoning, causing liver necrosis; and common flu drugs such as antitussives and antihistamines, causing gastrointestinal lesions with mydriasis, dry mucous membranes, disorientation and may show fever in cats and dogs (¹⁰,¹¹). Therefore, the potential for deliberate abuse of these drugs always exists and should always be considered when such poisoning is suspected. For this reason, this report aims to describe the clinical consequences of unprescribed use of Hedera helix extract as well as the case management.

Case Presentation

A 1-year-old, vaccinated, not neutered male Golden Retriever dog, weighing 24 kg, admitted to the Selcuk University Veterinary Faculty Animal Hospital with complaints of vomiting, diarrhea, anorexia and excessive salivation. In the anamnesis, it was learned that the dog lived at home, had not recently changed its diet and was fed commercial food, and was taken out for a walk twice a day. It was admitted to a veterinary clinic with a complaint of cough 2 months before the admission to our hospital, where it was diagnosed with tracheitis, and antibiotics (Ceftriaxone) and antitussives (Butamirate citrate) were prescribed. However, it was learned that the owner of the patient did not administer the prescribed drugs and gave Prospan® (Engelhard Arzneimittel GmbH & Co. KG, Germany) syrup to the dog 3 times a day for 30 days (total daily dose 105 mg).

In the clinical examination, abdominal pain, severe salivation and dehydration were detected along with normothermia. Following physical examination, blood samples were taken from the cephalic vein by venous puncture for blood gas test, complete blood count (CBC) and serum biochemistry. Fecal examination was performed to rule out the parasitic factors that could cause gastrointestinal symptoms such as vomiting, diarrhea and nausea. Canine Parvovirus (CPV), Canine Coronavirus (CCV) and Canine Distemper Virus (CDV) rapid tests (ASAN Pharm Easy Test®, Korea) were performed. Rapid test results were negative. No parasites were detected on fecal examination. Radiographic and ultrasonographic examinations were performed to rule out any suspicion of foreign body or invagination. No abnormal finding was observed. In the laboratory studies, mild metabolic acidosis and base deficit in blood gases and azotemia, a significant increase in AST, ALP, LDH and CPK enzyme levels in serum biochemistry were detected. CBC findings were within the normal reference range (Table 1).

For a symptomatic treatment, fluid therapy (0.9 % Isotonic solution, Polifleks, Polifarma®, 60 ml/kg IV, SID), antiemetic (Maropitant, Cerenia, Pfizer®, 1 mg/kg SC, SID), gastric protectant (Ranitidine, Ranixel, Menta Pharma®, 2mg/kg IV, BID), vitamin and mineral supplements (Duphalyte, Zoetis®, 10 ml/kg IV, SID) were administered intravenously for 3 days. Prospan® syrup was discontinued. Appetite was restored 3 days after the treatment and it was observed that all clinical symptoms resolved.

Based on clinical examination and laboratory tests, factors that could cause gastrointestinal disease symptoms such as kidney disease, liver disease, diabetic ketoacidosis, pancreatitis, parasitic, viral and bacterial factors, foreign bodies, and diet change were ruled out, and the cause of gastroenteritis was evaluated as Hedera helix extract poisoning.

Discussion and Conclusion

In the last few decades, there has been a rapid increase in the field of herbal medicine in both developed and developing countries due to its natural origin and fewer side effects. Metabolites used in many fields such as pharmacology, agrochemistry, color and food additives are obtained from plants. Hedera helix also contains a wide variety of metabolites and pharmacological agents. Its traditional use is the symptomatic treatment of cough in common flu and acute or chronic inflammatory bronchial diseases in humans. In addition, it has expectorant, analgesic, and anti-inflammatory effects. Preliminary studies on the phytochemical analysis of Hedera helix revealed that the plant contains unsaturated sterols, tannins, phenolic components, glycosides, alkaloids, carbohydrates, sugars and saponins. The concentration of 25-320 µM of α-hederin, one of these saponins, significantly changes the spontaneous motor activity of the smooth muscle in the rat stomach (¹²). Likewise, it was reported that daily oral use of 1.5 gr/kg dry ivy leaf for 100 days did not have hematological, biochemical, and histological effects in rats, but 4 gr/kg for 90 days of use had hemolytic effects (¹³).

Some investigators reported (²,¹⁴,¹⁵,¹⁶) that as dietary saponins are poorly absorbed, their biological effects occur in the gastrointestinal tract. Some saponins increase intestinal mucosal cell permeability in vitro, inhibit active mucosal transport and facilitate uptake of waste substances. An increase in the permeability of the brush border observed at sublethal levels of saponins may have important implications for the uptake of macromolecules, such as allergens, resulting in gastrointestinal signs such as vomiting and diarrhea.

There are several reported negative effects of saponins in single-stomached animals such as reduced feed intake caused by the irritating properties of saponins (¹⁷), reduction in the intestinal motility, reduction in protein digestibility (¹⁸) and damage to the intestinal membrane and inhibition of nutrient transport through intestinal tract (²). Lanza et al. (¹⁹) reported that oral use of ivy leaf dry extract (containing 66 % ethanol) in rats at a dose of 3-4.1 g/kg did not cause death in the first 72 hours, but caused diarrhea. On the other hand, oral use at a dose of 2.8-4.7 g/kg has been reported to cause death within the first 48 hours, and diarrhea was the only observed symptom before death. It is reported that dry extract of ivy leaf at an oral dose of 1.5 gr/kg daily for 100 days does not show toxic effects in rats. In the study, no abnormality was observed in any hematological and biochemical parameters and histopathological findings of the kidney and liver compared to the control group. Haemolytic effect has been reported in oral use of 4 gr/kg daily for 90 days as mentioned above.

In a study researching the toxicity and absorption kinetics of the triterpene saponins in mice and dogs, it was observed that the non-toxic intravenous dose for oleane triterpene saponin was 0.01 mg/kg and only minor effects were noted at 0.1 mg/kg. The liver is the primary target for toxicity with lesions such as focal hepatocellular necrosis. This is also reflected in the blood as a mild to moderate increase of the liver enzymes within 24 hours (²⁰). In the same study it was also determined that increase in the liver enzymes such as ALT, AST, ALP and pathological changes such as hepatocellular necrosis and vacuolization were the most significant toxic signs. The increase in AST ALT and ALP liver enzymes in our case can be attributed to liver parenchymal damage caused by syrup Hedera helix.

In this clinical report, gastroenteritis was attributed to the random and unprescribed administration by the owner of Prospan® syrup, which contains 0.7 g dry ivy helix folium extract in 30 % ethanol solvent. In this case, it was observed that daily oral use of Prospan® for 30 days at a dose of 4.3 mg/kg caused gastroenteritis in the dog, and that supportive treatment consisting of fluid therapy, antiemetic, gastric protectants and vitamin mineral supplements was sufficient to relieve clinical symptoms. The limitations of this case report are the fact that serum concentrations of triterpene saponins, the bioactive substance of Hedera helix, could not be determined and that the gastrointestinal mucosa and liver damage was not histopathologically evaluated. It was concluded that the successful management of Hedera helix extract poisoning depends on a differential diagnosis as gastroenteritis is a broad term and has many potential causes -being Hedera helix extract poisoning one of them- and requires quitting the use of syrup immediately and a supportive treatment. In addition, it is advisable to educate the public about the potential risks of over-the-counter drugs as it is usual for pet owners to give their pets the medicines they use for themselves.