Pizotifen

295.44

295.44

239-632-9

0BY8440V3N

DTXSID6023490

N - Nervous system

31.5

6.13

1.164±0.06 g/cm3(Predicted)

164 °C

436.7±45.0 °C(Predicted)

217.9±28.7 °C

1.631

Partly miscible in water.DMSO: ≥8mg/mL

Refrigerator

7.92E-08mmHg at 25°C

175.4 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]

NONH for all modes of transport

3

36/37/38-22-63

26-37/39-36/37

TM7165000

Xi,Xn

P281

H302-H361

|Warning|H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P264, P270, P281, P301+P312, P308+P313, P330, P405, and P501|Aggregated GHS information provided by 39 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The oral Lowest published toxic dose (TDLo) is 12.86 mg/kg in man [MSDS]. Oral LD50 ranges from 410 to 1500 mg/kg in rat [MSDS, L2292]. Oral LD50 in mouse and rabbit is 880 mg/kg and 700 mg/kg, respectively. The LD50 following intravenous administration in rat was 17 mg/kg. In adults, the symptoms of overdosage include sedation, drowsiness (preceding excitement, convulsions, and postictal depression), dizziness, hypotension, dryness of the mouth, confusion, tachycardia, ataxia, nausea, vomiting, dyspnea, cyanosis, convulsions, coma, respiratory paralysis and CNS depression. Antihistamine toxicity of pizotifen in children may involve excitation, hallucinations, ataxia, incoordination, convulsions, fixed dilated pupils, flushed faces, and fever, leading to coma and cardiorespiratory collapse. The use of activated charcoal is recommended in the management of overdose. For drug recent uptake, induction of emesis or gastric lavage and diuresis should be performed. Supportive measures should be initiated to maintain effective respiration while closely monitoring vital signs. While severe hypotension must be corrected, the use of adrenaline may produce paradoxical effects. As pizotifen has the potential to cause tachycardia, an ECG should be performed and attention directed at the QRS and QT intervals. Excitatory states or convulsions induced by pizotifen may be treated with short-acting barbiturates or benzodiazepines. However analeptics should be avoided.

Plasma protein binding of pizotifen is > 90%.

Indicated for the prophylactic management of migraines.

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.

A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS. (See all compounds classified as Analgesics, Non-Narcotic.)|Mood-stimulating drugs used primarily in the treatment of affective disorders and related conditions. Several MONOAMINE OXIDASE INHIBITORS are useful as antidepressants apparently as a long-term consequence of their modulation of catecholamine levels. The tricyclic compounds useful as antidepressive agents (ANTIDEPRESSIVE AGENTS, TRICYCLIC) also appear to act through brain catecholamine systems. A third group (ANTIDEPRESSIVE AGENTS, SECOND-GENERATION) is a diverse group of drugs including some that act specifically on serotonergic systems. (See all compounds classified as Antidepressive Agents.)|Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS. (See all compounds classified as Serotonin Antagonists.)

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%.|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.|The volume of distribution in an adult male is 833L for pizotifen and 70L for the N-glucuronide conjugate.

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.

The elimination half-life for pizotifen and N-glucuronide conjugate is about 23 hours.

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.

BC 105

Pharmaceuticals