Pizotifen API Manufacturers

General Description:

Pizotifen, identified by CAS number 15574-96-6, is a notable compound with significant therapeutic applications. Pizotifen belongs to the class of antamines and is related to . It is a potent serotonin and tryptamine antagonist that has been used for migraine prevention for many years. It exhibits weak anticholinergic, antihistamine, and antikinin actions in addition to sedative and appetite-stimulating properties . Some patients receiving pizotifen treatment developed tolerance with the prolonged use of the drug . Numerous studies have revealed the potential antidepressant effects of pizotifen, which are independent of its antimigraine action . While it is suggested that pizotifen may act similarly to the classic tricyclic antidepressants , its full mechanism of antidepressant action is not fully elucidated. Pizotifen hydrochloride is an active ingredient in Sandomigran, which is used for the prophylactic management of migraines. Sandomigran is available in a number of countries but is not approved by the FDA nor EMA.

Indications:

This drug is primarily indicated for: Indicated for the prophylactic management of migraines . Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Pizotifen undergoes metabolic processing primarily in: Pizotifen is extensively metabolized in the liver, where it primarily undergoes N-glucuronidation to form the main metabolite, N-glucuronide conjugate . N-glucuronide conjugate accounts for at least 50% of the plasma and 60-70% of the urinary-excreted radioactivity . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pizotifen are crucial for its therapeutic efficacy: The absorption half-life of pizotifen following oral administration is 0.5 to 0.8 hours in an adult male with nearly complete absorption rate of 80%. Maximum blood levels are reached 5 hours post-administration and the absolute bioavailability is 78% . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pizotifen is an important consideration for its dosing schedule: The elimination half-life for pizotifen and N-glucuronide conjugate is about 23 hours . This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pizotifen exhibits a strong affinity for binding with plasma proteins: Plasma protein binding of pizotifen is > 90% . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pizotifen from the body primarily occurs through: About one third of the total orally administered dose is excreted into the feces. Less than 1% of the total dose is excreted in the urine as the unchanged parent drug, and up to 55% of the dose is excreted as its metabolites . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pizotifen is distributed throughout the body with a volume of distribution of: The volume of distribution in an adult male is 833L for pizotifen and 70L for the N-glucuronide conjugate . This metric indicates how extensively the drug permeates into body tissues.

Pharmacodynamics:

Pizotifen exerts its therapeutic effects through: 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. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pizotifen functions by: 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 . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Pizotifen belongs to the class of organic compounds known as cycloheptathiophenes. These are polycyclic compounds containing a thiophene ring fused to a 7 member carbocyclic moiety. Thiophene is 5-membered ring consisting of four carbon atoms and one sulfur atom, classified under the direct parent group Cycloheptathiophenes. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Cycloheptathiophenes class, specifically within the None subclass.

Categories:

Pizotifen is categorized under the following therapeutic classes: Adrenergic alpha-1 Receptor Antagonists, Adrenergic alpha-Antagonists, Adrenergic Antagonists, Agents producing tachycardia, Agents that produce hypertension, Analgesics, Analgesics, Non-Narcotic, Anticholinergic Agents, Antidepressive Agents, Antimigraine Agents, Miscellaneous, Antimigraine Preparations, Central Nervous System Agents, Central Nervous System Depressants, Histamine Antagonists, Histamine H1 Antagonists, Muscarinic Antagonists, Nervous System, Neurotransmitter Agents, Peripheral Nervous System Agents, Psychotropic Drugs, Sensory System Agents, Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome, Serotonin 5-HT1 Receptor Antagonists, Serotonin 5-HT2 Receptor Antagonists, Serotonin 5-HT2A Receptor Antagonists, Serotonin 5-HT2C Receptor Antagonists, Serotonin Agents, Serotonin Receptor Antagonists, Sulfur Compounds, Thiophenes. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Pizotifen include:

• Water Solubility: Partly miscible