Apomorphine has a long and tortuous path in the therapeutic armamentarium, with numerous indications in human and veterinary medicine. |
The controversy that apomorphine aroused among clinicians in the past (and in some ways, continues among neurologists) can be explained by the lack of controlled studies and its affiliation to morphine. |
There are three main indications for apomorphine: emetic, sedative, and antiparkinsonian. |
This old drug needs to be reconsidered by clinicians and will benefit from current galenic and technical advances, both in Parkinson’s disease and in other indications. |
1 Introduction
Date | Author(s) | Discovery |
---|---|---|
1845 | Arppe (Finland) | First synthesis of apomorphine (morphine + sulfuric acid) |
1848 | Laurent & Gerhardt (France) | Apomorphine is named sulfomorphide |
1851 | Anderson (Scotland) | Apomorphine synthesized from codeine (+ sulfuric acid) |
1869 | Matthiessen and Wright (England) | Apomorphia synthesis (morphine + hydrochloric acid) |
1869 | Gee (England) | Emetic, stereotypogenic, sedative and excitatory properties (experiments on dogs and humans) |
1869 | Hare (England) | Treatment of alcoholism |
1870 | Pierce (England) | Beneficial on choreic movements in humans |
1871 | Siebert (Estonia) | Pharmacological study (humans, dogs, cats, frogs, rabbits) |
1874 | Harnack (Estonia) | Pharmacological study (mammals and frogs) |
1884 | Weill (France) | Apomorphine first suggested as a treatment for several motor disorders: chorea, shaking, and Parkinson’s disease |
1899 | Douglas (USA) | Powerful sedative properties (alcoholism) |
1902 | Pschorr et al. (Germany) | Apomorphine structure is elucidated |
1923 | Amsler (Austria) | Involvement of the striatum in apomorphine’s action |
1935 | Anderson (Canada) | Used in the treatment of paralysis agitans |
1951 | Schwab et al. (USA) | Short-lived but marked improvement in Parkinson’s disease |
1965 | Ernst et al. (The Netherlands) | Structure similar to dopamine (rats and rabbits) |
1966 | Ernst and Smelik (The Netherlands) | Site of action of apomorphine in rats: neostriatum |
1967 | Ernst (The Netherlands) | Apomorphine acts on dopaminergic receptors |
1967 | Andén et al. (Sweden) | |
1979 | Corsini et al. (Italy) | Combination of apomorphine and domperidone prevents nausea, drowsiness, sedation, and arterial hypotension |
1984 | Hardie et al. (England) | Apomorphine reverses parkinsonian off-phases when administered shortly after their onset |
1987 | Stibe et al. (England) | Subcutaneous infusion of apomorphine in the treatment of Parkinsonian on–off fluctuations |
1995 | Aguettant | Apokinon® 30 mg/3 mL authorization in France to treat Parkinson’s disease (pen) |
2001 | Tap Pharmaceutical/Abbot Laboratories | Uprima® (sublingual form of apomorphine) to treat erectile dysfunction |
2004 | FDA (USA) | FDA approval of Apokyn® as a rescue therapy in Parkinson’s disease to treat episodes of hypomobility |
2 Waterlilies and Aporphine Alkaloids: An Insight into Empirical Pharmacology
3 The 19th and 20th Centuries: From Apomorphine Synthesis to Understanding its Pharmacology
3.1 Synthesis
3.2 Milestones Along the Road to Understanding the Pharmacology of Apomorphine
3.2.1 Chemical Formula and Structure
3.2.2 Physiological Effects of Apomorphine
Humans | Rats | Mice | Dogs | Rabbits | Cats | Monkeys | Frogs | Pigeons | Guinea pigs | |
---|---|---|---|---|---|---|---|---|---|---|
Movement | ↓ Tremor in Parkinson’s disease | Stereotyped behaviors: sniffing and head and limb movements (low-intensity component), gnawing, licking, biting, (high-intensity component) | Stereotyped behaviors: sniffing, licking, biting | Stereotyped behaviors: incessant running in circles | Stereotyped behaviors: licking, gnawing. Muscle paralysis, respiratory failure, convulsions and death (highest doses) | Repetitive movements | Stereotypic behavior (> 200 µg/kg) | Motor stimulation followed by paralysis | Stereotyped behaviors: pecking (sometimes mistakenly referred to as a feeding hallucination) | Stereotyped behaviors: agitation, gnawing |
Body temperature | ↓ | ↓ | ↓ | ↓ | ↑ | ? | ? | ? | ? | ? |
Blood pressure | ↓ | ↓ | ? | ↓ | ↓ | ↓ | ? | ? | ? | ? |
Gastrointestinal tract | Nausea and emesis | Resistant to emesis ↑ Salivation | ? | Emesis (but tachyphylaxis to the emetic effect) | Resistant to emesis | Inconstant emesis | Resistant to emesis | Resistant to emesis | Inconstant emesis | ? |
Hormone release | ↑ Growth hormone ↓ Prolactin | ↓ Plasma prolactin concentration in intact male rats | ? | ↑ Gastrin | ? | ↑ Gastrin | ? | ? | ? | ? |
Heart rate and EEG changes | ↓ Inhibition of sympathetic cardiac nerve function | Desynchronization of EEG activity | ? | ↑ (But no change in noradrenaline plasma levels) Potentiates vagal bradycardia | ↓ | ↓ | ? | ? | ? | ? |
Central nervous system | Sedation Yawning Slight and transient delirium in one case of chronic Bright’s disease | Yawning Intraspecies aggression | ? | Nervousness or sedation, depending on the dose | Nervousness, agitation | Arousal | Yawning (25–100 µg/kg) Intraspecies aggression | ? | Arousal | Arousal |
Sexual behavior | Penile erections Spontaneous erections | Penile erections Spontaneous erections | Proerectile Genital grooming | ? | ? | ? | Penile erections, masturbation (50–200 µg/kg) | ? | ? | ? |
Others | Diaphoresis Dilatation of pupils | ? | ? | ? | ? | Pupil dilation | ? | ? | ? | ? |
References | [33] | [33] |