Background and overview[1]
Phenytoin Sodium (PHT-Na), also known as Dalentin, is the sodium salt of diphenylhydantoin and is the drug of choice for anti-epileptic grand mal seizures. Commonly used for anti-epilepsy, anti-arrhythmia, anti-trigeminal neuralgia, and anti-mild hypertension. Since PHT-Na has a wide range of biological activities and pharmacological therapeutic effects, it is often used in the treatment of other diseases in clinical practice. Many of its previous side effects have now been tried in the treatment of related diseases, and have achieved good results.
Preparation[2]
Tablets: 50mg, 100mg. Powder injection: 100mg, 250mg.
Function and purpose[1-2]
Diphenylhydantoin has a highly selective inhibitory effect on the motor areas of the cerebral cortex, preventing the propagation of abnormal discharges and thus anti-epileptic. Its mechanism of action has not been fully elucidated, but it may be mainly related to stabilizing cell membranes and reducing the spread of high-frequency discharges. It may also be related to the fact that this product can increase the content of the inhibitory transmitter γ-aminobutyric acid (GABA) in the brain. It has a good effect on major and localized seizures of epilepsy, followed by psychotic seizures, and is ineffective on minor seizures. It is also used in the treatment of trigeminal neuralgia and sciatica, antiarrhythmic and mild hypertension.
1. Promote wound healing
Phenytoin (diphenylhydantoin) was found to have the side effect of gingival hyperplasia in clinical application. In 1958, Shapiro first applied phenytoin (diphenylhydantoin) to the treatment of gingival wounds. , found that phenytoin can indeed promote wound healing. It has been clinically reported to be used in the treatment of wound healing, and has achieved ideal results. Research over the past decade has proven that the main mechanisms by which phenytoin (diphenylhydantoin) promotes wound healing include the following aspects: ① Reduce the inflammatory response of the wound. Phenytoin (diphenylhydantoin) stabilizes lysosomal membranes, resists lipid peroxidation, and inhibits the production of prostaglandins. In clinical application, it can often reduce local pain, edema, and reduce inflammatory exudation. ②Accelerate the growth of granulation tissue. Phenytoin can reduce the synthesis and release of collagenase, promote the proliferation of fibroblasts, activate macrophages, and enhance the activity level of growth factors. During application, it can accelerate the growth of granulation tissue, improve local blood circulation, and accelerate wound healing. ③ Reduce wound infection. Phenytoin (diphenylhydantoin) is an alkaline drug, which changes the local pH value of the wound, making the wound unfavorable for the growth of bacteria; phenytoin (diphenylhydantoin) accelerates the growth of granulation tissue and enhances local Anti-infection ability: Phenytoin (diphenylhydantoin) has a direct inhibitory effect on Gram-negative bacilli. After application of phenytoin (diphenylhydantoin), most wound bacteria can be reduced or negative. Based on this, phenytoin sodium (diphenylhydantoin) has been widely used in lower limb ulcers, osteomyelitis sinus tracts, leprosy ulcers, diabetic skin ulcers, oral ulcers, bedsores, surgical wound healing and traumatic wound healing after cervical cancer radiotherapy. Difficulties, etc., have achieved good results. In recent years, the combination of 0.5% povidone-iodine solution and phenytoin (diphenylhydantoin) can more effectively improve the efficacy of delayed healing wounds and is used for the treatment of delayed healing wounds. In addition, studies have shown that phenytoin sodium (diphenylhydantoin) has a significant inhibitory effect on gastric ulcers caused by glacial acetic acid in rats, and its protective effect is similar to that of ranitidine, suggesting that it may be used in the healing treatment of gastric ulcers. It also has a certain promoting effect.
2. Treatment of migraine
Research has proven that phenytoin (diphenylhydantoin) is effective as a bioelectric modulator in the treatment of migraine, especially in migraine patients with neurosis. The experiment found that the effective rate for typical migraine and atypical migraine was 74.36%, and all patients with effective neurosis treatment had effective migraine treatment. The pathogenesis of migraine is related to the increase in vasoactive substances, sudden activation of neuronal activity in the brain, or direct action on adrenergic nerve endings, and is related to endogenous adjustment of pain signal transmission in the central nervous system (CNS). related to changes in the level of mechanisms. Foreign studies have confirmed that pain is closely related to axonal firing and synaptic transmission. The effect of phenytoin is directly proportional to axonal firing and synaptic transmission. That is, the more firing, the greater the effect, because it increases the stability of the membrane and reduces the risk of pain. concentration does not interfere with normal function, but when neurons are more sensitive than normal, such as in the case of local trauma and ischemia, phenytoin (diphenylhydantoin) has special protective functions, thereby reducing pain reduce or disappear. In recent years, it has been reported that the use of acupuncture combined with the Western medicines Sibirine and Phenytoin (diphenylhydantoin) to treat migraine has also achieved satisfactory results, and the efficacy is better than acupuncture alone and Western medicine alone.
3. Treatment of vertigo
Recent studies have shown that phenytoin (diphenylhydantoin) can also be used clinically as an anti-vertigo drug. The anti-vertigo effect of phenytoin (diphenylhydantoin) may also be due to its stabilizing effect on the membranes of the central and peripheral nerves, just like lidocaine. Phenytoin (diphenylhydantoin) stabilizes the membrane potential mainly by increasing the active influx of K+ and the active outflow of Na+, thereby regulating nerve function and reducing inner ear edema. This�Sodium hydroxide forms a salt to form phenytoin (diphenylhydantoin). The reaction formula for synthesizing phenytoin sodium (diphenylhydantoin) is as follows:
1) Synthesis of benzoin
Add 0.8g vitamin B1, 2mL distilled water and 8mL 95% ethanol into a 25mL three-necked flask, place the three-necked flask in ice water and cool to 0°C. Add 2 mL of 10% sodium hydroxide solution in ice bath dropwise into the three-necked flask, adjust the pH of the reaction solution to about 9, add 5 mL of benzaldehyde, and adjust to maintain the pH of the reaction solution at about 9. Install a reflux condensation device on the three-neck flask and heat to reflux for 1.5 hours. During reflux, changes in the pH value of the reaction solution should be observed at any time. An appropriate amount of 2 mol·mL-1 sodium hydroxide solution can be added to keep the pH value of the reaction solution between 8 and 10. Cool to room temperature and put in ice water to cool. At this time, light yellow crystals will slowly precipitate to complete the crystallization. Filter with suction, wash the crystals with cold distilled water, recrystallize with 95% ethanol, and dry to obtain 2.32g of benzoin, with a yield of 44.4%.
2) Synthesis of benzophenone
Add 9.5g ferric chloride, 11mL glacial acetic acid, and 6mL distilled water into a 50mL three-neck flask. After refluxing for 5mi, add 2.5g of benzoin and allow it to reflux for 1h. After the reflux is completed, cool to room temperature, then put in ice water to cool and crystallize. Yellow crystals slowly precipitate. When the crystallization is complete, the crystals are obtained by suction filtration and recrystallized with 95% ethanol. After drying, 1.63g of the product is obtained, with a yield of 66.0%. .
3) Synthesis of phenytoin (diphenylhydantoin)
Add 2.0g benzoethylene glycol, 10mL 95% ethanol, 20mL distilled water, 1.0g urea into a 100mL round-bottomed flask. After heating, add 6mL 20% sodium hydroxide solution in batches to make it Completely dissolved, color changes from light yellow to brown. Then install the reflux device, stir and heat to reflux for 80 minutes. After the reaction is completed, pour 30 mL of boiling water, add activated carbon, boil for 10 minutes, and filter while hot. When the filtrate reaches about 40°C, use 10% hydrochloric acid to adjust the pH to about 6, let it cool and precipitate crystals, filter them with suction, and wash the crystals with a small amount of water to obtain 2.40g of crude phenytoin. Add crude phenytoin and 10 mL distilled water to a 100 mL round-bottomed flask, warm to about 45°C on a water bath, and add 20% sodium hydroxide solution dropwise with stirring until the suspension is completely dissolved (the pH is between 11 and 12 at this time) ), put in activated carbon and continue to heat and decolorize for 5 minutes, filter while hot, transfer the filtrate obtained to a 100mL beaker, put it in the refrigerator to cool and crystallize, filter with suction, and dry to obtain 0.81g of phenytoin sodium (diphenylhydantoin), yield is 30.8%.
Main reference materials
[1] Overview of clinical application of phenytoin (diphenylhydantoin)
[2] General Practitioner Medication Manual
[3] Synthesis of phenytoin
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