Voltage-gated Na+ channels (VGSCs)

One anti-oxidant medication is phenytoin. It is ineffective for original comprehensive advantages like the Absence Plan or muscle matrix tonics, but it is helpful for direct matrix tonics with powerful partial and comprehensive effects. It is believed that phenytoin achieves this by voltage gating. Channels can be blocked by voltage to stop programming [2]. Low neuronal affinity for resting channels at supra-thigh membrane potential is exhibited by phenytoin [3]. More binding and blocking happen when the channel and the upper portion of the metaphase change to an open, inactive state. Because the blocking effect is very usage dependent, it builds up after extended or frequent activation, like when a reference occurs. Since phenytoin's blocking of sodium channels acts slowly, it does not quickly alter the current time course or burst the strongest event potentials that are broken down by synapses of ordinary duration. Therefore, without significantly affecting ictal activity, phenytoin can occasionally decrease pathological hyperexcitability in phase patients. Additionally, phenytoin causes electrical current to burst continuously, which may be crucial for managing engineering data. One class 1b antiarrhythmic medication is phenytoin [4].

Phenytoin (5,5-diphenylhydantoin; 60 mg/kg; daily; 28 days) decreases the formation of tumors in female Rag2-/-Il2rg-/- mice that are six weeks old by employing MDA-MB-231 cells [1].

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Limbic epileptogenesis alters the anticonvulsant efficacy of phenytoin in Sprague-Dawley rats[6].

Phenytoin is found to bind tightly to the fast inactivated state of sodium channels but binding occurs slowly, a key characteristic enabling phenytoin to disrupt epileptic discharges with minimal effects on normal firing activity.[5]
The anticonvulsant phenytoin inhibited Na+ currents in rat hippocampal neurons with a potency that increased dramatically at depolarized holding potentials, suggesting weak binding to resting Na+ channels but tight binding to open or inactivated channels. Four different experimental measurements, i.e., steady block at different holding potentials, on and off kinetics at depolarized holding potentials, shifts in the inactivation curve, and dose-dependent slowing of recovery from inactivation, yielded an estimated Kd of approximately 7 microM for phenytoin binding to inactivated channels. Prolonged depolarizations of at least several seconds were necessary for significant block by therapeutic concentrations of phenytoin. The slow development of block does not reflect selective binding of phenytoin to slow inactivated states of the channel, because block developed faster and required less depolarized voltages than did slow inactivation. Instead, it appears that phenytoin binds tightly but slowly (approximately 10(4) M-1 sec-1) to fast inactivated states of the Na+ channels. This tight but slow binding may underlie the ability of phenytoin to disrupt epileptic discharges with minimal effects on normal firing patterns.[5]

In this study, the effects of phenytoin sodium on the quantal content of e.p.ps were investigated in excised mouse sternomastoid nerve-muscle preparations. On exposure to a solution containing phenytoin sodium (10 pg/ml) the mean amplitude of e.p.ps was reduced. It was found that the concentration of phenytoin sodium tested significantly reduced the time constant of decay of m.e.p.cs but had little effect on their amplitude. Decay of m.e.p.cs there appeared to be a reduction in the growth time of m.e.p.cs in the presence of the phenytoin. In the three experiments, the growth time fell from 175 + 19 ms in control solution to 146 + 10 ms in the solution containing phenytoin. A. The results show that phenytoin has two types of depressant action at the neuromuscular junction. [7]

We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen. Conclusions: This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.[1]

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Studies on the anticonvulsant efficacy of the major antiepileptic drug phenytoin in kindled rats have often reported inconsistent effects. It has been proposed that technical and genetic factors or poor and variable absorption of phenytoin after i.p. or oral administration may be involved in the lack of consistent anticonvulsant activity of phenytoin in this model of temporal lobe epilepsy. We examined if kindling itself changes the anticonvulsant efficacy of phenytoin by testing this drug before and after amygdala kindling in male and female Sprague-Dawley rats. To exclude the possible bias of poor and variable absorption, blood was sampled in all experiments for drug analysis in plasma. The threshold for induction of focal seizures (afterdischarge threshold; ADT) was used for determining phenytoin's anticonvulsant activity. Before kindling, phenytoin, 75 mg/kg i.p., markedly increased ADT in both genders, although the effect was more pronounced in males. Following kindling, the anticonvulsant activity obtained with phenytoin, 75 mg/kg, before kindling was totally lost, and female rats even exhibited a proconvulsant effect upon administration of this dose, indicating that kindling had dramatically altered the anticonvulsant efficacy of phenytoin. Plasma levels of phenytoin were comparable before and after kindling, and were within or near to the 'therapeutic range' known from epileptic patients. When the dose of phenytoin was reduced to 50 or 25 mg/kg i.p., significant anticonvulsant effects on ADT were obtained. When phenytoin, 50 mg/kg, was administered i.p. or i.v. in the same group of fully kindled rats, both anticonvulsant activity and plasma drug levels were comparable with both routes, indicating that the i.p. route is suited for such studies. The data indicate that kindling alters the dose-response of phenytoin in that a high anticonvulsant dose becomes ineffective or proconvulsant after kindling, possibly by an increased sensitivity of the kindled brain to proconvulsant effects of phenytoin which normally only occur at much higher doses. If similar alterations evolve in humans during development of chronic epilepsy, this may be involved in the mechanisms leading to intractability of temporal lobe epilepsy.[6]

Absorption, Distribution and Excretion
Given its narrow therapeutic index, therapeutic drug monitoring is recommended to help guide dosing. Phenytoin is completely absorbed. Peak plasma concentration is attained approximately 1.5-3 hours, and 4-12 hours after administration of the immediate release formulation and the extended release formulation, respectively. It should be noted that absorption can be markedly prolonged in situations of acute ingestion.
The majority of phenytoin is excreted as inactive metabolites in the bile. An estimated 1-5% of phenytoin is eliminated unchanged in the urine.
The volume of distribution of phenytoin is reported to be approximately 0.75 L/kg.
The clearance of phenytoin is non-linear. At lower serum concentrations (less than 10 mg/L), elimination is characterized by first order kinetics. As plasma concentrations increase, the kinetics shift gradually towards zero-order, and finally reach zero-order kinetics once the system is saturated.
Studies using Dilantin have shown that phenytoin and its sodium salt are usually completely absorbed from the GI tract. Bioavailability may vary enough among oral phenytoin sodium preparations of different manufacturers to result in toxic serum concentrations or a loss of seizure control (subtherapeutic serum concentrations)...
Absorption of phenytoin is slow and variable among products (poor in neonates) for oral admininstration, immediate for iv administration, and very slow but complete (92%) for intramuscular administration.
Prompt phenytoin capsules are rapidly absorbed and generally produce peak serum concentrations in 1.5-3 hours, while extended phenytoin sodium capsules are more slowly absorbed and generally produce peak serum concentrations in 4-12 hours. When phenytoin sodium is administered im, absorption may be erratic; this may result from crystallization of the drug at the injection site because of the change in pH.
/Phenytoin/ is distributed into cerebrospinal fluid, saliva, semen, GI fluids, bile, and breast milk; it also crosses the placenta, with fetal serum concentrations equal to those of the mother.
For more Absorption, Distribution and Excretion (Complete) data for PHENYTOIN (15 total), please visit the HSDB record page.

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Metabolism / Metabolites
Phenytoin is extensively metabolized and is first transformed into a reactive _arene oxide intermediate_. It is thought that this reactive intermediate is responsible for many undesirable phenytoin adverse effects such as hepatotoxicity, SJS/TEN, and other idiosyncratic reactions. The _arene oxide_ is metabolized to either a _hydroxyphenytoin_ or _phenytoin dihydrodiol_ metabolite, although the former accounts for about 90% of phenytoin metabolism. Interestingly, two stereoisomers of the _hydroxyphenytoin_ metabolite are formed by CYP2C9 and CYP2C19: _(R)-p-HPPH_ and _(S)-p-HPPH_. When CYP2C19 catalyzes the reaction, the ratio of stereoisomers is roughly 1:1, whereas when CYP2C9 catalyzes the reaction, the ratio heavily favours the "S" stereoisomer. Since the metabolism of phenytoin is in part influenced by genetic polymorphisms of CYP2C9 and CYP2C19, this ratio can be utilized to identify different genomic variants of the enzymes. EPHX1, CYP1A2, CYP2A6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 are responsible for producing the _phenytoin dihydrodiol_ metabolite. _Hydroxyphenytoin_ can be metabolized by CYP2C19, CYP3A5, CYP2C9, CYP3A4, CYP3A7, CYP2B6 and CYP2D6 to a _phenytoin catechol_ metabolite or undergo glucuronidation by UGT1A6, UGT1A9, UGT1A1, and UGT1A4 to a _glucuronide metabolite_ that can be eliminated in the urine. On the other hand, the _phenytoin dihydrodiol_ entity is only transformed to the _catechol_ metabolite. The _catechol metabolite_ can undergo methylation by COMT and be subsequently eliminated in the urine, or can spontaneously oxidize to a _phenytoin quinone_ (NQO1 can transform the quinone back to the catechol metabolite). Of note, although CYP2C18 is poorly expressed in the liver, the enzyme is active in the skin and is involved in the primary and secondary hydroxylation of phenytoin. This CYP2C18 mediated bioactivation may be linked to the manifestation of adverse cutaneous drug reactions associated with phenytoin.
The major route of metabolism of phenytoin is oxidation by the liver to the inactive metabolite 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Because this metabolism is a saturable process, small increases in dosage may produce substantial increases in plasma phenytoin concentrations...
The rate of hepatic biotransformation is increased in younger children, in pregnant women, in women during menses, and in patients with acute trauma; rate decreases with advancing age. The major inactive metabolite of phenytoin is 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Phenytoin may be metabolized slowly in a small number of individuals due to genetic predisposition, which may cause limited enzyme availability and lack of induction.
... Oxidative metabolism of 1 of geminal phenyl rings of diphenylhydantoin ... 5-meta-hydroxyphenyl-(l) and 5-para-hydroxyphenyl-5-phenylhydantoin were detected in urine of man (approx ratio 1:12) ...
Phenytoin has known human metabolites that include 3'-HPPH, 4-Hydroxyphenytoin, 5-(3,4-dihydroxycyclohexa-1,5-dien-1-yl)-5-phenylimidazolidine-2,4-dione, and (2S,3S,4S,5R)-6-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)-3,4,5-trihydroxyoxane-2-carboxylic acid.
Primarily hepatic. The majority of the dose (up to 90%) is metabolized to 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). This metabolite undergoes further glucuronidation and is excreted into the urine. CYP2C19 and CYP2C9 catalyze the aforementioned reaction.
Route of Elimination: Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion.
Half Life: 22 hours (range of 7 to 42 hours)

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Biological Half-Life
Oral administration: The half-life of phenytoin ranges from 7 to 42 hours, and is 22 hours on average. Intravenous administration: The half-life of phenytoin ranges from 10-15 hours.
Following oral administration, the plasma half-life of phenytoin averages about 22 hours, although the half-life has ranged from 7-42 hours in individual patients. The plasma half-life of phenytoin in humans following IV administration ranges from 10-15 hours.
Because phenytoin exhibits saturable, zero-order, or dose-dependent pharmacokinetics, the apparent half-life of phenytoin changes with dose and serum concentrations. this is due to the saturation of the enzyme system responsible for metabolizing phenytoin, which occurs at therapeutic concentrations of the drug. Thus, a constant amount of drug is metabolized (capacity-limited metabolism), and small increases in dose may cause disproportionately large increases in serum concentrations and apparent half-life, possibly causing unexpected toxicity.

Hepatotoxicity
Prospective studies indicate that a fairly high proportion of patients taking phenytoin have transient serum aminotransferase elevations. These elevations are usually benign, not associated with liver histological abnormalities and usually resolve even with drug continuation. In addition, a higher proportion of patients have mild-to-moderate elevations in gammaglutamyl transpeptidase (GGT) levels, which is indicative of hepatic enzyme induction rather than liver injury. Marked aminotransferase elevations (>3 fold elevated) occur rarely.
Importantly, however, phenytoin is one of the most common causes of clinically apparent drug induced liver disease and acute liver failure. More than 100 cases of liver injury due to phenytoin (diphenylhydantoin) have been published and a characteristic clinical pattern (signature) of injury has been described. The estimated frequency ranges from 1 per 1000 to 1 per 10,000 and probably varies by race and ethnicity. The typical case arises after 2 to 8 weeks of therapy with initial onset of fever, rash, facial edema and lymphadenopathy, followed in a few days by jaundice and dark urine. The serum enzyme elevations can be hepatocellular, although mixed patterns are probably more common and rare cases are cholestatic. Eosinophilia, increased white counts and atypical lymphocytosis are also common. Autoantibody formation is rare. The clinical symptoms and signs can mimic acute mononucleosis or even lymphoma (pseudo-lymphoma syndrome). Almost all cases of phenytoin hepatotoxicity occur in the context of a systemic hypersensitivity syndrome and it is referred to often as the anticonvulsant hypersensitivity syndrome (HDS) or drug rash with eosinophilia and systemic symptoms syndrome (DRESS). Other manifestations can be Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, thrombocytopenia, neutropenia, nephritis, and pneumonitis. Most cases of liver injury are self-limiting and resolve within 1 to 2 months of stopping phenytoin. However, the liver injury can be severe and many fatal instances have been reported, phenytoin usually appearing in the top 10 causes of drug induced acute liver failure. In the typical case, however, recovery is usually complete.
Likelihood score: A (well known cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Breastfeeding during phenytoin monotherapy does not appear to adversely affect infant growth or development, and breastfed infants had higher IQs and enhanced verbal abilities than nonbreastfed infants at 6 years of age in one study. If phenytoin is required by the mother, it is not a reason to discontinue breastfeeding.
Because of the low levels of phenytoin in breastmilk, amounts ingested by the infant are small and usually cause no difficulties in breastfed infants when used alone except for rare idiosyncratic reactions. Combination therapy with sedating anticonvulsants or psychotropics may result in infant sedation or withdrawal reactions. In one case report, maternal phenytoin dosage requirements decreased as breastfeeding was discontinued.
◉ Effects in Breastfed Infants
A mother was taking phenobarbital 390 mg daily and phenytoin 400 mg daily during pregnancy and postpartum. Her infant was drowsy at birth, refused to suck and was given partial formula feeding. At 5 days of age, her infant was admitted to the hospital pale and collapsed with bruising, bleeding, and a decreased hemoglobin, thought to be due to methemoglobinemia. Breastfeeding was discontinued and the infant was given a transfusion which rapidly improved her condition. On day 10, the mother resumed breastfeeding the infant. Within 24 hours the infant was extremely sedated and refused to suck and was fed breastmilk with a spoon. The sedation persisted for 2 days until breastmilk was discontinued permanently because of a return of methemoglobinemia. The extreme sedation was probably due to phenobarbital in the milk and the methemoglobinemia was probably caused by the phenytoin.
One clinician reported that the breastfed infants of 28 mothers who were taking phenytoin 100 to 200 mg 3 times daily had no adverse reactions including drowsiness or lethargy.
No adverse effects were noted in the breastfed neonates of 2 mothers who were taking phenytoin 300 mg daily.
A 10-week-old breastfed infant whose mother was taking clemastine, phenytoin and carbamazepine was drowsy, refused to feed, was irritable, and had high-pitched crying. These side effects were possibly caused by clemastine in breastmilk, but the other drugs could also have contributed.
A probable case of drug-induced drowsiness occurred in a newborn whose mother was taking primidone, carbamazepine and phenytoin (dosages not stated). On day 30, breastfeeding was discontinued because of the drowsiness that occurred after each feeding and poor weight gain. The same group of researchers found that 15 partially breastfed infants whose mothers were taking various anticonvulsants, including phenytoin, gained weight at a slower rate during the first 5 days postpartum than did 75 infants of epileptic mothers who bottle fed or control mothers taking no medications.
Drowsiness, pallor and feeding difficulties in a 2-week-old were possibly caused by primidone and phenytoin in breastmilk. Possible drug-related drowsiness, pallor and feeding difficulties were reported in a 4-day-old whose mother was taking primidone, phenobarbital, phenytoin and sulthiame. Although phenytoin might have contributed to these outcomes, it is more likely that they were due primarily to the more sedating anticonvulsants, primidone and phenobarbital.
Two breastfed infants (one full, one partial) whose mothers took phenytoin during pregnancy and postpartum became hyperexcitable when their serum phenytoin dropped to unmeasurable levels at 3 to 6 weeks of age.
In a long-term study on infants exposed to anticonvulsants during breastfeeding, no difference in average intelligence quotient at 3 years of age was found between infants who were breastfed (n = 17) a median of 6 months and those not breastfed (n = 23) when their mothers were taking phenytoin. At 6 years of age, extensive psychological and intelligence testing found no difference between the breastfed and nonbreastfed infants.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Phenytoin is roughly 90% protein bound.

[1] The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis. Mol Cancer. 2015 Jan 27;14(1):13.
[2]. The neurobiology of antiepileptic drugs. Nat Rev Neurosci, 2004. 5(7): p. 553-64.
[3]. Mechanisms of action of antiseizure drugs. Handb Clin Neurol, 2012. 108: p. 663-81.
[4]. Medical therapy for sudden death. Pediatr Clin North Am, 2004. 51(5): p. 1379-87.
[5]. Slow binding of phenytoin to inactivated sodium channels in rat hippocampal neurons. Mol. Pharmacol. 46, 716–725 (1994).
[6]. Limbic epileptogenesis alters the anticonvulsant efficacy of phenytoin in Sprague-Dawley rats. Epilepsy Res. 31, 175–186 (1998).
[7]. Presynaptic and postsynaptic depressant effects of phenytoin sodium at the neuromuscular junction. Br J Pharmacol . 1980 May;69(1):119-21.

Diphenylhydantoin (Phenytoin) can cause cancer and developmental toxicity according to an independent committee of scientific and health experts.
Phenytoin appears as fine white or almost white crystalline powder. Odorless or almost odorless. Tasteless. (NTP, 1992)
Phenytoin is a imidazolidine-2,4-dione that consists of hydantoin bearing two phenyl substituents at position 5. It has a role as an anticonvulsant, a teratogenic agent, a drug allergen and a sodium channel blocker. It is functionally related to a hydantoin.
Phenytoin is classified as a hydantoin derivative and despite its narrow therapeutic index, it is one of the most commonly used anticonvulsants. Since it's introduction about 80 years ago, phenytoin has not only been established as an effective anti-epileptic, but has also been investigated for several other indications such as bipolar disorder, retina protection, and wound healing. Clinicians are advised to initiate therapeutic drug monitoring in patients who require phenytoin since even small deviations from the recommended therapeutic range can lead to suboptimal treatment, or adverse effects. Both parenteral and oral formulations of phenytoin are available on the market.
Phenytoin is an Anti-epileptic Agent. The mechanism of action of phenytoin is as a Cytochrome P450 1A2 Inducer, and Cytochrome P450 2B6 Inducer, and Cytochrome P450 2C8 Inducer, and Cytochrome P450 2C19 Inducer, and Cytochrome P450 2D6 Inducer, and Cytochrome P450 3A Inducer, and Cytochrome P450 2C9 Inducer. The physiologic effect of phenytoin is by means of Decreased Central Nervous System Disorganized Electrical Activity.
Phenytoin, formerly known as diphenylhydantoin, is a potent anticonvulsant used to treat and prevent generalized grand mal seizures, complex partial seizures and status epilepticus. Phenytoin was formerly the most commonly used anticonvulsant agent but is now declining in use, having been replaced by more modern, better tolerated agents. Phenytoin is an uncommon but well known cause of acute idiosyncratic drug induced liver disease that can be severe and even fatal.
Phenytoin Sodium is the sodium salt form of phenytoin, a hydantoin derivate and non-sedative antiepileptic agent with anticonvulsant activity. Phenytoin sodium promotes sodium efflux from neurons located in the motor cortex, thereby stabilizing the neuron and inhibiting synaptic transmission. This leads to a reduction in posttetanic potentiation at synapses, an inhibition of repetitive firing of action potentials and ultimately inhibits the spread of seizure activity.
Phenytoin is a hydantoin derivative and a non-sedative antiepileptic agent with anticonvulsant activity. Phenytoin potentially acts by promoting sodium efflux from neurons located in the motor cortex reducing post-tetanic potentiation at synapses. The reduction of potentiation prevents cortical seizure foci spreading to adjacent areas, stabilizing the threshold against hyperexcitability. In addition, this agent appears to reduce sensitivity of muscle spindles to stretch causing muscle relaxation.
An anticonvulsant that is used in a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.
An anticonvulsant that is used to treat a wide variety of seizures. It is also an anti-arrhythmic and a muscle relaxant. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. The mechanism of its muscle relaxant effect appears to involve a reduction in the sensitivity of muscle spindles to stretch. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.
See also: Phenytoin Sodium (annotation moved to).

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Drug Indication
Phenytoin is indicated to treat grand mal seizures, complex partial seizures, and to prevent and treat seizures during or following neurosurgery. Injectable phenytoin and [Fosphenytoin], which is the phosphate ester prodrug formulation of phenytoin, are indicated to treat tonic-clonic status epilepticus, and for the prevention and treatment of seizures occurring during neurosurgery.

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Mechanism of Action
Although phenytoin first appeared in the literature in 1946, it has taken decades for the mechanism of action to be more specifically elucidated. Although several scientists were convinced that phenytoin altered sodium permeability, it wasn’t until the 1980’s that this phenomenon was linked to voltage-gated sodium channels. Phenytoin is often described as a non-specific sodium channel blocker and targets almost all voltage-gated sodium channel subtypes. More specifically, phenytoin prevents seizures by inhibiting the positive feedback loop that results in neuronal propagation of high frequency action potentials.
The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. In neurons, phenytoin decreases sodium and calcium ion influx by prolonging channel inactivation time during generation of nerve impulses. Phenytoin blocks the voltage-dependant sodium channels of neurons and inhibits the calcium flux across neuronal membranes, thus helping to stabilize neurons. It also decreases synaptic transmission, and decreases post-tetanic potentiation at the synapse. Phenytoin enhances the sodium ATPase activity of neurons and/or glial cells. It also influences second messenger systems by inhibiting calcium-calmodulin protein phosphorylation and possibly altering cyclic nucleotide production or metabolism.
Phenytoin may act to normalize influx of sodium and calcium to cardiac Purkinje fibers. Abnormal ventricular automaticity and membrane responsiveness are decreased. Also, phenytoin shortens the refractory period, and therefore shortens the QT interval and the duration of the action potential.
Exact mechanism is unknown. Phenytoin may act in the CNS to decrease synaptic transmission or to decrease summation of temporal stimulation leading to neuronal discharge (antikindling). Phenytoin raises the threshold of facial pain and shortens the duration of attacks by diminishing self-maintenance of excitation and repetitive firing.
Phenytoin's mechanisms of action as a muscle relaxant is thought to be similar to its anticonvulsant action. In movement disorders, the membrane stabilizing effect reduces abnormal sustained repetitive firing and potentiation of nerve and muscle cells.
A number of studies suggest that keratinocyte growth factor (KGF) plays a major part in reepithelialization after injury, via binding to the specific KGF receptor (KGFR). Several pharmacological agents, including the anti-epileptic drug phenytoin (PHT), have been widely used clinically to promote wound healing. Although the mechanism of action of PHT in this process is still not well understood, it is possible that the activity of PHT in wound healing is mediated via KGF and the KGFR. In the present study, using the enzyme-linked immunosorbant assay and flow cytometry we have shown that PHT increases KGF secretion and KGFR expression by more than 150% in gingival fibroblasts and epithelial cells, respectively. Moreover, semi-quantitative reverse transcriptase-polymerase chain reaction analysis showed that PHT also markedly increased both KGF and KGFR gene transcription by these cells.

C₁₅H₁₂N₂O₂

252.27

252.089

C, 71.42; H, 4.79; N, 11.10; O, 12.68

57-41-0

Phenytoin sodium;630-93-3;Phenytoin-d10;65854-97-9;Phenytoin-15N2,13C;78213-26-0; 57-41-0

1775

White to off-white solid powder

1.3±0.1 g/cm3

464.0±55.0 °C at 760 mmHg

293-295 °C(lit.)

305.8±20.8 °C

0.0±1.2 mmHg at 25°C

1.652

2.29

2

2

2

19

350

0

CXOFVDLJLONNDW-UHFFFAOYSA-N

InChI=1S/C15H12N2O2/c18-13-15(17-14(19)16-13,11-7-3-1-4-8-11)12-9-5-2-6-10-12/h1-10H,(H2,16,17,18,19)

2,4-Imidazolidinedione, 5,5-diphenyl-

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.91 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.91 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)