APITOFEN® SYRUP

Indications

• Support in energy metabolism
• Management of metabolic disorders
• Potential role in exercise performance enhancement

Dosage

Children: Refer to specific guidance in the BNF for Children.

Adults: Refer to specific guidance in the BNF.

Mechanism of action

Malate participates in the malate-aspartate shuttle, which is essential for transferring reducing equivalents across the mitochondrial membrane. This shuttle allows for the conversion of NADH produced during glycolysis to NADH within the mitochondria, thus facilitating ATP production. Additionally, malate is involved in gluconeogenesis, where it contributes to the synthesis of glucose from non-carbohydrate precursors.

Pharmacodynamics

Malate aids in energy metabolism, particularly in the conversion of nutrients to ATP. It supports the regeneration of NAD+, which is crucial for numerous metabolic reactions. By participating in the TCA cycle, malate enhances aerobic respiration and plays a role in maintaining the balance of metabolic intermediates necessary for cellular function.

Pharmacokinetics

Malate is readily absorbed in the gastrointestinal tract and is distributed throughout the body, where it enters various metabolic pathways. It is primarily metabolized in the liver and muscle tissues. The elimination of malate is through metabolic conversion, with its metabolites being further processed in the TCA cycle.

Pregnancy

There are no well-controlled studies of malate in pregnant women. Use only if clearly needed.

Breast-feeding

Malate is considered to be safe during breastfeeding, though limited data are available.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Malate salts
• Malic acid

Indications

• Prevention of vascular headache
• Prevention of classical migraine
• Prevention of common migraine
• Prevention of cluster headache

Dosage

Children: Child 5–17 years: Initially 500 micrograms once daily, dose to be taken at night, then increased if necessary up to 1.5 mg daily in divided doses, with gradual increases and a maximum single dose at night of 1 mg.

Adults: Initially 500 micrograms once daily, then increased to 1.5 mg once daily, or alternatively increased to 1.5 mg daily in 3 divided doses, with gradual increases as necessary up to a maximum of 4.5 mg daily (max. per dose 3 mg).

Mechanism of action

Pizotifen is proposed to inhibit peripheral actions of serotonin and histamine, affecting membrane permeability of cranial vessels and transudation of plasmakinin. By blocking 5-HT receptors, it attenuates serotonin-induced cranial vasoconstriction and platelet aggregation. It may also inhibit serotonin reuptake by blood platelets, impacting the tonicity of extracranial arteries.

Pharmacodynamics

Studies have shown pizotifen to be effective in preventing migraines, significantly reducing the frequency and severity of vascular headaches. It acts as an antagonist to postsynaptic 5-HT2 receptors and histamine H1 receptors, with additional weak anticholinergic properties. Pizotifen has shown interaction with adrenergic and dopamine receptors and exhibits minimal sedative effects.

Pharmacokinetics

Pizotifen is well absorbed after oral administration, with a peak plasma concentration achieved within a few hours. It is metabolized in the liver and has a relatively long half-life, allowing for once-daily dosing in many cases. The drug's pharmacokinetic profile suggests a steady-state concentration can be reached after several days of consistent dosing.

Contra-indications

• Acute porphyrias

Adverse effects

• Drowsiness
• Weight gain
• Constipation
• Aggression
• Anxiety
• Arthralgia
• Depression
• Hallucination
• Muscle complaints
• Paraesthesia
• Seizure
• Skin reactions
• Bleeding
• Sleep disorders
• Hepatic disorders

Interactions

• Antihistamines, sedating

Precautions

• Avoid abrupt withdrawal
• History of epilepsy
• Susceptibility to angle-closure glaucoma
• Urinary retention
• Use with caution in hepatic impairment
• Use with caution in renal impairment

Pregnancy

Avoid unless potential benefit outweighs risk.

Breast-feeding

Amount probably too small to be harmful, but manufacturer advises avoid.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets: 1.5 mg

Mechanism of action

While the mechanism of action is not fully understood, it is proposed that pizotifen works by inhibiting the peripheral actions of serotonin and histamine in increasing the membrane permeability of cranial vessels and transudation of plasmakinin, while altering pain thresholds in migraines. By blocking 5-HT receptors, pizotifen attenuates the signalling of serotonin in causing cranial vasoconstriction, as well as serotonin-enhanced platelet function and aggregation. There is evidence that it also inhibits the peripheral actions of bradykinin. Pizotifen may inhibit serotonin reuptake by blood platelets, which affects the tonicity and decreases passive distension of extracranial arteries. The effects of pizotifen leading to appetite stimulation may be due to the drug acting at the metabolic level rather than a direct stimulation of the appetite centre.

Pharmacodynamics

Various studies have shown pizotifen to be effective in the prophylaxis of migraines in reducing the frequency and severity of vascular headaches. Evidence from studies _in vivo_ and _in vitro_ demonstrate antagonistic actions towards serotonin and histamine. Pizotifen blocks the postsynaptic 5-HT2 receptors, as supported by antagonism of several direct agonists of 5-HT receptors. It is an antagonist at histamine H1 receptors, and is weakly anticholinergic. It also binds to α1- and α2-adrenergic receptors, and dopamine receptors. Pizotifen elicits a minimal effect as an epinephrine or bradykinin antagonist. Pizotifen exhibits weak sedative properties in mouse and monkey studies, as indicated by inhibition of locomotion and potentiation of barbiturates, without changes in cardiac or respiratory rates. In dogs, intravenous administration of pizotifen cause rapid hypotension but was reversed to normal within 30 minutes. Pizotifen was shown to inhibit serotonin uptake in the isolated perfused cat spleen and, _in vivo_, inhibits serotonin-induced contractions in rat uterus and cat nictiating membrane. In contrast, pizotifen demonstrated a venoconstrictor activity _in vivo_ when orally or intravenously administered to saphenous veins in conscious dogs. Pizotifen has the potential to stimulate the appetite and may cause weight gain upon treatment. In a double-blind clinical study of patients with mild to moderate depression, treatment of pizotifen led to clinical improvement of the depressive symptoms. However, deterioration of the schizophrenic emotional symptoms was also observed in patients with depression and chronic schizophrenia. This indicates that pizotifen may potentially improve the symptoms of patients with depressions in conjunction with migraines. Neuroprotective effect of pizotifen was investigated _in vitro_ in a mouse cell model of Huntington's disease (HD). According to a chemical screen of a mouse HdhQ111/Q111 striatal cell model of HD, treatment of pizotifen was associated with increased ATP levels and decreased activation of caspase-3, leading to enhanced cell viability. Transient activation of ERK signalling pathway lasting for less than 3 hours was also observed. In the R6/2 transgenic mouse model of HD, rotarod performance of the mouse treated with pizotifen was seen, accompanied by an increase in DARPP-32 protein expression and restoration of striatal area. However these effects being reflected _in vivo_ are not established.