Swiss Parkinsonian Association supports self-help groups and informs the public

Dopamine preparations and enzyme inhibitors combat a progressive disease

The central event in Parkinson’s disease is progressive death of cells of the substantia nigra in the midbrain. This disturbs the balance between the neurotransmitters dopamine and acetylcholine. The disease affects some 250,000 people in Germany and some 12,000 people in Switzerland. The typical features of the disease include slowing of movements, stiffness of certain muscles, and often a rhythmical tremor of the hands and feet. Treatment generally consists of an L-dopa preparation in combination with another type of drug. The Roche drug Madopar® has proved their worth in the treatment of Parkinson’s disease.

1. Instead of a heroin “hit”, a fatal shaking palsy

In 1817, in his “essay on the shaking palsy”, the British physician James Parkinson described in detail the signs and symptoms of the disease that was later to bear his name. At the time, however, Parkinson was unable to offer any effective treatment. Years later, the French neurologist Jean M. Charcot and his coworkers looked more closely at the possibilities for drug treatment of the syndrome and recommended the use of atropine.

Between 1917 and 1927 the worldwide spread of “Spanish flu” — named after its country of origin — brought Parkinson’s disease to the attention of the public at large. The virus responsible for this pandemic caused encephalitis lethargica, a type of inflammation of the brain that led to Parkinson’s disease as a late complication in a very high proportion of patients. Millions of people were affected and many of these required long-term care in sanatoria and nursing homes.

More recently, another incident led to increased research into Parkinson’s disease. In the early 1980s some young drug addicts who were attempting to manufacture a substitute for heroin made a serious mistake. Instead of obtaining the desired designer drug, they unwittingly obtained a toxic byproduct and then proceeded to inject themselves with this. Within a few days many of them had developed the full-blown clinical picture of Parkinson’s disease as a result of degeneration of the substantia nigra (black substance) in the midbrain. A parkinsonian syndrome can also be induced by carbon disulfide and carbon monoxide, by manganese, lead, and cyano compounds, by tumours in the region of the basal ganglia, and by head injuries.

Studies on the brains of deceased parkinsonian patients have shown that Parkinson’s disease is due to a disturbance of the basal ganglia. These are groups of nerve cells the coordinated activity of which is required for normal muscular tonus, smooth execution of slow movements, and coordinated action of different groups of muscles. Like the cerebellum, they are connected to the motor part of the cerebral cortex and with it are responsible for the execution of complex movements. Within the basal ganglia various groups of nerve cells exert continuous control over each other’s activity. Notable among these are the substantia nigra and in particular the (corpus) striatum (striped body). The substantia nigra contains neurons whose axons inhibit the activity of striatal neurons, and thus ultimately activate motor functions, by releasing the neurotransmitter dopamine. Among the cells that counterbalance this action are those that release acetylcholine as a transmitter substance. A reduction in the amount of dopamine shifts the balance in the striatum in favour of acetylcholine and thus leads to inhibition of muscular movements.

Patients with Parkinson’s disease suffer degeneration not just of the cells of the substantia nigra, but also of the connections between these cells and the striatum. By the time the first symptoms appear, however, some 70 to 80 percent of the cells concerned have already been destroyed.

2. Symptom triad of akinesia, rigor, and tremor

Parkinson’s disease is characterised by various signs and symptoms, though not all of these are present in all patients. The reduction in general motor activity manifests itself especially in the patient’s gait (poverty of movement, akinesia). The step becomes shorter and the gait shuffling. Walking may be preceded by hesitation, but once in motion the patient may find it difficult to stop and tends to fall forwards. A characteristic feature that is present both when standing still and when walking is the stooped posture with bent knees and elbows.

The typical muscular tension or rigidity sometimes results in jerky resistance to passive flexion or extension of the limbs. Although this “cogwheel” phenomenon is absent in 20 to 30 percent of cases, the tremor that is partially responsible for it is a very typical feature of Parkinson’s disease. This is a trembling of the upper limbs when at rest that is present particularly in the early stages of the disease.

The most severe disturbance of mobility is the “on-off phenomenon”, in which the patient passes abruptly from a state of good mobility (on) to one of complete rigidity (off).

Most patients also show poverty of facial expression leading to a mask-like facies. This impression is reinforced by infrequency of blinking. The patient’s speech sounds monotonous and becomes soft, rapid, and unintelligible.

Patients can also develop a variety of more or less severe autonomic symptoms. Prominent among these are nocturnal sweating, increased secretion of sebum (seborrhea) leading to oily skin, constipation, difficulty in passing urine, and in male patients erectile dysfunction. Depression is common. Memory, concentration, reasoning, and perceptive capacity may be impaired.

3. Lack of dopamine as the cause

Parkinsonism is characterised biochemically by a deficiency of the neurotransmitter dopamine. This substance is synthesised in a series of steps from the amino acid phenylalanine, which is present in food. After passing from the blood into the brain, phenylalanine is converted into tyrosine. This in turn is converted by tyrosine hydroxylase into L-dopa (dihydroxyphenylalanine). L-dopa is then converted into dopamine by the enzyme L-dopa decarboxylase (DDC). The dopamine is then stored in tiny vesicles in the axons of dopaminergic nerve cells, i.e. nerve cells that use dopamine as a messenger substance (neurotransmitter).

Transmission of an impulse from one dopaminergic nerve cell to another involves release of dopamine into the synaptic cleft between the two cells and passage of this dopamine across the synaptic cleft to binding sites (receptors) on the cell receiving the impulse. Binding of dopamine to dopamine receptors D1 and D2 is a precondition for normal bodily movement. Binding to an “autoreceptor” controls the concentration of dopamine and ensures that not too much of it is released.

After exerting its action on the receptors, dopamine can either be taken back up into the vesicles or broken down to inactive compounds by enzymes, of which there are two, namely catechol-O-methyltransferase (COMT), which converts dopamine into 3-methoxytyramine, and monoamine oxidase B (MAO-B), an enzyme found mostly in the glial cells of the striatum that converts dopamine to dihydroxyphenylacetic acid (DOPAC).

4. Effective drugs

The drug therapy of Parkinson’s disease aims firstly to replace or strengthen the effect of dopamine, and secondly to weaken the dominant effect of acetylcholine.

As exogenously administered dopamine is unable to cross the blood-brain barrier, L-dopa, the immediate physiological precursor of dopamine, is used instead. After oral administration this is absorbed through the intestine into the blood and from there enters the brain. A decarboxylase inhibitor is generally administered at the same time in order to reduce conversion of the L-dopa into dopamine in the periphery.

Larodopa®, Roche’s first levodopa preparation, was introduced as long ago as 1970. The year 1973 saw the introduction of Madopar®, which in addition to L-dopa contains the dopa decarboxylase inhibitor benserazide. Since then the formulation of this drug has been constantly improved. Since 1997 it has been available in Switzerland as Madopar DR® (dual release), a formulation that combines a rapid onset of action with high bioavailability. This three-layered matrix tablet releases L-dopa in high concentrations within an hour and then continuously over six hours. This has a steadying effect particularly on the “on-off” phenomenon.

5. Swiss Parkinsonian Association continues to help

In addition to drugs, patients with Parkinson’s disease need understanding, support, and practical help from those around them. The Swiss Parkinsonian Association, which was formed in 1985, provides counselling and information for patients and their families, supports the work of over 40 parkinsonian self-help groups in Switzerland, and issues a news sheet at three-monthly intervals. It works together with other specialised organisations, informs the public about the disease and about the needs of patients, organises accompanied holidays for patients, and supports research projects on Parkinson’s disease.

Roche Pharma Switzerland Ltd (RPS) offers a broadly based therapeutic approach in which drugs and other measures complement each other and in which patients, physicians, and the pharmaceutical industry work in close cooperation. Together with the Swiss Parkinsonian Association, RPS founded the interest group Patient im Alltag® (the patient in everyday life) as a means of supporting all efforts aimed at helping parkinsonian patients and their families cope with the everyday aspects of the disease.

Metabolic pathways of levodopa