Fixed Combinations of Pheasant's Eye fluidextract, Lily-of-the-valley powdered extract, Squill powdered extract, and Oleander leaf powdered extract

Published September 24, 1993.
List of German Commission E Monographs (Phytotherapy)

Name of Drug

Fixed combinations of Pheasant's Eye fluidextract, Lily-of-the-valley powdered extract, Squill powdered extract, and Oleander leaf powdered extract.

Composition of Drug

Fixed combinations consisting of:

Pheasant's Eye fluidextract obtained by extracting the herb with 80 percent ethanol after preconditioning with 80 percent ethanol and calcium hydroxide (herb: native extract = 3.2:1). The extract contains at least 0.1 percent total glycosides calculated as cymarin, determined as the sum of all glycosides obtained by HPLC. Total glycosides comprise 3 - 20 percent adonitoxin and 1 - 10 percent cymarin. The fluidextract has a potency on guinea pigs of 1.2 - 9.6 mg/g (related to cymarin).

Lily-of-the-valley dry extract obtained by extracting the herb after preconditioning with 92 - 96 percent ethanol and calcium hydroxide (herb: native extract=14.5 - 17.5:1). The dry extract contains at least 0.4 percent total glycosides calculated as convallatoxin, determined as the sum of all glycosides obtained by HPLC. The total glycosides comprise 4 - 35 percent convallatoxin, 1.5 - 20 percent sarhamnolosid, 10 - 20 percent desglucocheirotoxol and 1 - 25 percent desglucocheirotoxin. The dry extract has a potency on guinea pigs of 6.2 - 37.2 mg/g (related to convallatoxin).

Squill bulb fermented with water and then extracted with ethyl acetate (herb: native extract=1000:1). The extract is concentrated and again extracted with ethanol; the residue of the ethanol extract is used. The extract contains at least 25 percent total glycosides calculated as proscillaridin A, determined as the sum of all glycosides obtained by HPLC. The total glycosides comprise 35 - 60 percent proscillaridin A, 8 - 25 percent 19-oxo-proscillaridin and a maximum of 8 percent of other glycosides. The dry extract has a potency on guinea pigs of 346-968 mg/g (related to proscillaridin A).

Oleander dry extract obtained by extracting the leaves after fermentation with water and calcium hydrox-ide (herb: native extract=10 - 12:1). The dry extract contains at least 1 percent total glycosides calculated as oleandrin, determined as the sum of all glycosides obtained by HPLC. The total glycosides comprise 10-45 percent oleandrin and a maximum of 5 percent gentiobiosyloleandrin. The dry extract has a potency on the guinea pig of 3.45 - 20.7 mg/g (related to oleandrin).

The extracts were mixed corresponding to the guinea pig units (GPU) of 25:15:25:25. The dosage determination of the various forms of administration was based on the experimentally defined therapeutic value of the extract mixture. The formulation of the combinations is as follows:

Solid, single dosed preparations:

25 GPU Pheasant's Eye fluidextract equivalent to 0.03 mg total glycosides, calculated as cymarin; 5 GPU Lily-of-the-valley dry extract equivalent to 0.005 mg total glycosides, calculated as convallatoxin; 25 GPU Squill dry extract equivalent to 0.009 mg total lycosides, calculated as proscillaridin A; 25 GPU Oleander dry extract equivalent to 0.004 mg total glycosides, calculated as leandrin; Liquid, not individualized dosage forms/100 ml:

5000 GPU Pheasant's Eye fluidextract equivalent to 5.99 mg total glycosides, calculated as cymarin; 3125 GPU Lily-of-the-valley dry extract equivalent to 0.97 mg total glycosides, calculated as convallatoxin; 5000 GPU Squill dry extract equivalent to 1.73 mg total glycosides, calculated as proscillaridin A; 5000 GPU Oleander dry extract equivalent to 0.86 mg total glycosides, calculated as leandrin. Pharmacological Properties, Pharmacokinetics, Toxicology The principal glycoside of Pheasant's Eye herb is cymarin, of Lily-of-the-valley leaf is convallatoxin, of Squill is proscillaridin A, and of Oleander leaf is oleandrin. The actions of cardiac glycosides on the heart are:

positive inotropic (increasing contractile strength and velocity while delaying relaxation), negative chronotropic (decreasing the time or rate of contraction), negative dromotropic (decreasing stimulus conduction), positive bathmotropic (increasing stimulation of the ventricular muscle).

Pharmacokinetics

Cymarin:

The indication for the absorption of cymarin lies between 15 and 47 percent. The half-life of elimination is given as 13-23 hours. Elimination of cymarin occurs mainly by renal discharge. The subsidence rate is 50 percent. Recent investigations, particularly of the substance reacting in combinations, are not available.

Convallatoxin:

For convallatoxin an absorption rate of 10 percent and a subsidence rate of 40 - 50 percent are given. The absorption rate is supposedly increased by saponins contained in the herb. No information is available concerning its metabolism in humans. A renal/biliary excretion is assumed. The binding to plasma proteins lies between 16 and 23 percent. Recent investigations, particularly of the substance reacting in combinations, are not available.

Proscillaridin A:

Proscillaridin A is absorbed at a rate of 20 - 30 percent. The half-life value is 45 - 50 hours. The plasma protein binding is about 85 percent. Proscillaridin A is removed by biliary excretion after conjugation with glucuronic and sulfuric acid. There is an indication for an enterohepatic circulation. Recent investigations, particularly of the substance reacting in combinations, are not available.

Oleandrin:

For oleandrin, an absorption rate of 86 percent is given. Recent investigations, particularly of the substance reacting in combinations, are not available.

Clinical Data Uses Mild, limited heart action and circulatory instability.

Contraindications

Heart insufficiency NYHA functional levels III and IV, therapy with digitalis glycosides, digitalis intoxication, hypercalcemia, potassium deficiency, bradycardia, ventricular tachycardia.

Side Effects

Nausea, vomiting, gastric disorders, diarrhea, irregular pulse, and cardiac dysrhythmia may occur.

Special Caution for Use

Caution in case of stimulus conduction disorders and i.v. calcium therapy.

Use During Pregnancy and Lactation

None known.

Interactions with Other Drugs

Increased effectiveness and thus also increased side effects with concurrently administered quinidine, calcium, saluretics, laxatives, and long-term therapy with glucocorticoids.

Dosage

Unless otherwise prescribed:

Daily dosage of adults:
Solid, individually dosed preparations:

equivalent to 270 - 540 GPU; Liquid, not individually dosed preparations:

equivalent to 310 GPU. Mode of Administration Aqueous-alcoholic solutions and solid preparations for oral use.

Overdosage

Corresponding overdosage will result in basically the same symptoms as obtained with digitalis intoxication.

Main symptoms are disturbances of the heart rhythm, gastrointestinal and central nervous symptoms.

The sequence of therapeutic action depends on the severity of intoxication. For slight overdosing, discontinuation of the glycoside and careful monitoring of the patient would be sufficient.

Influences which lead to changes in digitalis tolerance are to be avoided or corrected (disturbances of the electrolyte, acid and base balance)

Patients with dangerous cardiac irregularity should be admitted to intensive care units and placed on monitors.

Depending on clinical situations, the following drugs may be administered:

For hypokalemia, the serum potassium level must be raised to the high normal range (KI:AV-block). In the case of severe intoxication, often dangerous hyperkalemia occurs initially. For the treatment of this hyperkalemia, intravenous infusions of high concentrations of glucose with insulin are indicated. For complex ventricular arrhythmias, diphenylhydantoin (phenyltoin sodium) or lidocaine should be administered. For bradycardiac rhythmic disturbances, parasympatholytics are applied, e.g., atropine, ipatropium bromide. If necessary, a transvenous pacemaker is temporarily implanted. Life-threatening intoxications:

Ingestion of extreme dosages, accidentally or with suicidal intent, basic poison elimination is indicated: irrigation of the stomach after initial application of atropine, followed by active charcoal, cholestyramin or cholestipol. Forced diuresis, peritoneal- and hemodialysis have proven to be unsuccessful for digoxin elimination.

Special Warnings

None known.