Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
140
W. Jing et al.
X Huo etal. [291] explored the efcacy of various antiepileptic medications in
preventing early and late posttraumatic epilepsy. Their analysis included 7 randomized controlled trials and 18 nonrandomized controlled trials encompassing
six interventions: phenytoin + phenobarbital, levetiracetam, phenytoin, a
phenytoin- levetiracetam combination, lacosamide, and valproate. The results
indicated that all interventions, except sodium valproate, signicantly reduced the
incidence of early posttraumatic epilepsy compared to that in the placebo group in
patients with traumatic brain injury. Additionally, four treatments (phenytoin+phenobarbital, levetiracetam, phenytoin, and sodium valproate) signicantly
decreased the occurrence of late seizures in these patients. Phenytoin did not
affect mortality rates; however, it was associated with a greater incidence of treatment-related adverse effects than was the placebo.
K Panda P etal. [292] conducted a systematic review of the relevant literature
to compare the effectiveness and safety of phenytoin and lacosamide in controlling seizures and improving short-term/long-term function in patients with status
epilepticus. Their ndings indicated that both drugs demonstrated comparable
efcacy, while phenytoin exhibited a greater incidence of serious side effects.
Consequently, it can be inferred that lacosamide may serve as a suitable alternative to phenytoin in status epilepticus, offering similar effectiveness with improved
tolerability.
Evidence-Based Medical Research onPhenytoin Sodium
Robin Ferner etal. [293] conducted a systematic review to identify the clinical and
radiological characteristics and associations of phenytoin’s effects on the cerebellum. They analyzed 92 patients, 81 of whom exhibited one or more clinical symptoms, such as ataxia (96%), dysarthria (63%), and nystagmus (70%). Radiological
assessment revealed cerebellar atrophy in 41 of 61 patients (67%). Their ndings
suggested that most patients with cerebellar dysfunction had phenytoin concentrations exceeding the reference range. Moreover, clinical signs of ataxia can persist
even in the absence of radiographic evidence of cerebellar atrophy, and cerebellar
atrophy can occur without any clinical evidence of cerebellar dysfunction. Clinical
evidence indicates that phenytoin can induce the metabolism of voriconazole,
potentially leading to reduced efcacy. The coadministration of voriconazole with
phenytoin necessitates doubling the voriconazole dose to maintain therapeutic levels. Voriconazole can elevate phenytoin levels, resulting in increased C
and AUC
max
values of approximately 70% and 80%, respectively. These ndings underscore the
importance of cautious use of voriconazole in patients undergoing phenytoin treatment for epilepsy [294].
Effects ofPhenytoin Sodium onBrain Electricity andCognitive Function
Cognitive changes associated with ASMs treatment in children with epilepsy
were thoroughly investigated by Besag FMC etal. [78] through a comprehensive PubMed literature review. Cognitive impairment is a common occurrence
2 Antiseizure Medications
141
in patients with epilepsy, and ASMs may contribute to or exacerbate this condition. Conversely, some ASMs may have positive effects on cognition. However,
reliable data on cognitive decits in pediatric patients are scarce for most ASMs,
including phenytoin. Despite its extensive history of use, the cognitive effects of
phenytoin in pediatric patients have not been extensively studied. In a randomized comparison involving 64 children undergoing regular cognitive assessments, phenytoin and 2- propylvalerate were not associated with adverse
cognitive effects. However, phenytoin was observed to induce greater motor and
mental task impairment than CBZ, with these effects persisting even after discontinuation of the drug. Although there is a surprising lack of pediatric studies
on the cognitive effects of phenytoin, the available evidence suggests that it may
impair neurocognitive function. To address this gap, future studies evaluating
ASMs in young adults should incorporate standardized measures of cognition
and behavior.
Other Research
A retrospective analysis by A Muñoz-Vendrell etal. [295] examined 121 patients
with acute exacerbation of trigeminal neuralgia admitted to a tertiary hospital’s
emergency department from 2012 to 2020. These patients received intravenous
phenytoin or lacosamide for the rst time, and the efcacy and safety of intravenous lacosamide and phenytoin for treating acute trigeminal neuralgia were
evaluated. Among the 81 patients who received phenytoin injections, 72.8%
experienced pain relief, with 12.3% experiencing mild adverse reactions.
Specically, adverse reactions included dizziness, nausea, hypotension, infusion pain, skin rash, abnormal sensation, and pruritus, with some patients experiencing multiple symptoms simultaneously. The study concluded that
intravenous lacosamide and phenytoin administration are effective and safe
treatments for acute trigeminal neuralgia.
M Karaźniewicz-Łada etal. [116] reviewed recent data on ASMs and their interactions with other medications, nutrients, and food. Phenytoin was found to reduce
the levels of various medications, including calcium channel blockers, digoxin,
quinidine, hormonal contraceptives, proton pump inhibitors, ibrutinib, nilotinib,
sirolimus, and several statins. During the SARS-CoV-2 pandemic, concerns arose
regarding the interaction of phenytoin with antiretroviral drugs used to treat
COVID-19. Combining phenytoin with lopinavir/ritonavir led to a 30% reduction in
antiretroviral drug levels. Consequently, patients with COVID-19 and epilepsy may
require a 50% increase in the dose of lopinavir/ritonavir to maintain therapeutic levels.
142
W. Jing et al.
2.1.1.8 Nitrazepam
Drug Characteristics
[Chemical name] 5-Phenyl-7-nitro-1,3-dihydro-2H-1,4-benzodiazepine-2-one
[Chemical structure]
[Molecular formula] C15H11N3O3
[Molecular weight] 281.27
[Indications] (1) Treatment of insomnia and convulsions; (2) Second-line adju-
vant drug for various types of epilepsy and adjuvant treatment for different types of
refractory epilepsy; mainly used for petit mal seizures, especially myoclonic seizures and infantile spasms.
[Specications] 5mg 10mg
[Dosage] 15–30mg/day
The dosage varies depending on the ailment being addressed. When treating
insomnia, the recommended dosage is 5–10mg to be taken orally before bedtime.
For individuals with severe insomnia, especially among psychiatric patients, an
effective therapeutic dosage is 20mg to be taken orally before sleep. However,
adverse reactions and side effects, including severe hangovers, may manifest at this
dosage, thereby limiting its application. Regarding convulsions, the recommended
dosage for adults ranges from 10 to 20mg, while for children, it ranges from 5 to
10mg, depending on the cause, whether it is fever-induced or due to poisoning. For
epilepsy, the recommended dosage is 5–10mg (1–2 tablets) taken three times daily.
Children are typically administered a daily dosage of 0.5–3.5 mg/kg, with an
2 Antiseizure Medications
143
average of 1.5mg/kg, divided into two doses per day. The maintenance dose is usually 5–10mg/day. For muscle spasms, the recommended dosage is 2–15mg/day to
be taken orally in divided doses. In cases of severe spasticity, such as cerebral palsy,
the dosage may be increased to 60mg/day for adults and 40mg/day for children.
Patients with low tolerance to this medication should begin with a small initial dose
to mitigate the risk of addiction from prolonged heavy use. After prolonged administration, it is advisable to gradually taper the dosage to prevent withdrawal symptoms. Abrupt cessation should be avoided, particularly for epilepsy patients, as it
may precipitate status epilepticus.
[Adverse reactions] The most common adverse reactions to this product are
drowsiness, sedation, muscle weakness, ataxia, disorientation and behavioral disorders. These adverse reactions are caused by the suppression of the central nervous
system and can be gradually tolerated and alleviated with continued treatment. Less
common adverse reactions include headache, dizziness, confusion, depression,
slurred speech or dysarthria, changes in libido, tremor, visual disturbances, acral
paresthesia, urinary retention or incontinence, gastrointestinal disorders, decreased
appetite, decreased salivary secretion, excessive bronchial secretions, decreased
calculation ability, and memory impairment. Rash, liver damage, and bone marrow
suppression are occasionally observed. After taking the drug, patients may experience nightmares, hangover reactions, hostility, aggressive behavior and behavioral
disinhibition. High-dose parenteral administration may occasionally cause respiratory depression and hypotension. Patients with chronic obstructive bronchitis may
experience aggravated respiratory failure symptoms when using this drug. There
have been reports of dysphagia, aspiration pneumonia, and death in infants and
children after using this product. The side effects of this product are almost always
dose-dependent and disappear with a temporary dose reduction or discontinuation
of treatment. The main side effects of long-term use are tolerance and dependence.
Stopping use of the drug may produce mild but obvious withdrawal symptoms, and
a series of disease syndromes may also occur. Therefore, the dosage should be
adjusted slowly during use and formulated according to the patient’s response. An
individualized medication regimen is needed.
Clinical Application andBasic Research
Historical Evolution ofNitrazepam
Nitrazepam is a benzodiazepine drug that was rst described as a hypnotic drug in
1969. In 1975, it was reported that nitrazepam could be used as a treatment for children with infantile spasms and myoclonic quiescent seizures [296]. In 1977, L
Kangas etal. reported that the half-life of nitrazepam in plasma ranged from 16.5 to
48.3h (mean 28.8h) [297]. In 1981, A B Khrana etal. discovered that nitrazepam
can treat mood disorders in children [298]. In 1998, Ebata etal. reported that nitrazepam could reduce the frequency of nocturnal scratching in adults with atopic dermatitis [299]. In 2022, nitrazepam was recognized as a safe and viable alternative
144
W. Jing et al.
treatment option for children with drug-resistant West syndrome [300]. Recently,
nitrazepam has obtained approval from the Central Drug Standards Organization in
India for the treatment of epilepsy. However, it has not received approval from the
US Food and Drug Administration (FDA) for marketing in the United States due to
the presence of small quantities excreted into breast milk.
An Observational Study ofNitrazepam intheTreatment ofEpilepsy
Zhongshu etal. conducted a study focusing on phenylketonuria (PKU) and its association with West syndrome (WS-PKU) to explore the incidence and clinical characteristics of WS-PKU, as well as the signicance of early combined therapy
involving a hypophenylalanine (PHE) diet alongside use of ASMs. Their ndings
revealed that the onset of spasms began to diminish upon initiation of the diet, but
recurrences were frequent (78%) in the absence of ASMs [301]. However, the recurrence rate of seizures signicantly decreased to 18.2% when valproic acid or nitrazepam was administered concurrently with the diet. Another extensive retrospective
study conducted by Kaushik etal. examined children with West syndrome. This
study utilized a retrospective chart analysis of children who were diagnosed with
West syndrome between January 2008 and January 2012 and whose clinical proles
and treatment outcomes were documented at a tertiary care center in northern India.
Among the 148 children included (120 boys), the mean (SD) ages at onset and onset
of spasms were 5.3 (4.6) months and 13.1 (7.3) months, respectively. Perinatal
asphyxia (61.4%), neonatal sepsis/meningitis (10.6%), and postnatal meningitis
(11.4%) were identied as the primary causes, while the cause remained undetermined in 16.6% of the patients. The rate of cessation of spasms among 45 children
(30.4%) treated with prednisolone was 25.4%. The nal outcome was not inuenced by factors such as age at onset, sex, treatment delay, the presence of perinatal
asphyxia, or comorbid cerebral palsy [302].
Nitrazepam Is Added fortheTreatment ofRefractory Epilepsy
Beran suggested that stress can act as a catalyst for seizures, and benzodiazepines
offer a dual advantage by alleviating anxiety and elevating the seizure threshold in
individuals with epilepsy. Many patients attributed their seizures to stress without
realizing the connection until after the event. To validate this correlation and enable
preemptive measures, meticulous diaries must be maintained and reviewed.
Intermittent use of benzodiazepines, such as clobazam, clonazepam, diazepam, or
nitrazepam, can effectively prevent subsequent seizures and should be continued for
a period even after the risk diminishes [303].
Nitrazepam fortheTreatment ofEpilepsy Syndrome
Iyer etal. conducted an overview of emerging treatment strategies for infantile spasms,
particularly in the context of West syndrome, a prevalent epileptic encephalopathy.
Early identication and intervention can enhance neurodevelopmental outcomes in
2 Antiseizure Medications
145
some cases. Currently, corticosteroids, adrenocorticotropic hormone (ACTH), or
prednisolone, in combination with vigabatrin, are the preferred initial treatment
options. Combining steroids with vigabatrin may offer greater efcacy in suppressing
spasms and normalizing EEG patterns. Additional ASMs, such as levetiracetam,
nitrazepam, valproate, topiramate, and zonisamide, are commonly used as adjunctive
therapies in refractory patients who are resistant to initial treatment or who are experiencing spasm recurrence. Nitrazepam, a benzodiazepine anticonvulsant, is rarely
used in epilepsy treatment compared to clobazam and clonazepam. Its primary application is managing infantile spasms, with reported efcacy rates of up to 35% in
observational studies. The typical starting dose is 0.2 mg/kg/day and gradually
increases to 1–1.5mg/kg/day. However, adverse effects such as excessive drooling,
sedation, and hypotonia may restrict its use to a few weeks or months. Alternative
medications for refractory patients include sodium valproate, topiramate, and
zonisamide [304]. Hosain etal. described positive outcomes in 14 patients with drugresistant Lennox–Gastaut syndrome, suggesting that nitrazepam serves as an effective
adjunctive ASMs for managing mixed seizures in refractory patients. Unlike other
benzodiazepines, its efcacy and tolerability remain consistent over time, making it a
preferred option for patients with Lennox–Gastaut syndrome [305]. Tan Wang etal.
similarly noted that nitrazepam offers a safe and viable treatment approach for children with tolerable West syndrome, resulting in sustained relief from spasms and electroclinical response improvement in nearly half of the patients.
Nitrazepam intheTreatment ofRefractory andSuper Refractory Status
Epilepticus
Kagitani-Shimono etal. investigated the trajectory of epilepsy, seizure manifestations, and effective pharmacotherapy in patients with Wolf-Hirschhorn syndrome
through an examination of 11 patients (ranging from 2 to 25years old, with a mean
age of 7.2years). This syndrome is commonly associated with intractable seizures
and episodes of status epilepticus. Febrile or afebrile seizures were prevalent among
all patients, encompassing alternating hemiplegic seizures, generalized tonic–clonic
seizures, focal clonic seizures, tonic–clonic seizures, and epileptic spasms. The
authors noted a gradual reduction in seizure frequency and seizure burden in most
individuals with Wolf-Hirschhorn syndrome after the age of 5. However, during
infancy, status epilepticus can lead to irreversible impairment or even mortality.
Sodium bromide is recommended as an initial therapeutic option to prevent the
onset of status epilepticus linked to Wolf–Hirschhorn syndrome [306].
The Use ofNitrazepam inSpecial Populations withEpilepsy
Shields etal. documented a case involving a 6-month-old with asthma who developed spasticity and prominent arrhythmias on EEG shortly after commencing oral
theophylline therapy. Theophylline levels were slightly elevated at that time. Upon
discontinuation of theophylline and initiation of nitrazepam therapy, spasticity
ceased, and the EEG returned to baseline. Nitrazepam was tapered by 10months of
146
W. Jing et al.
age, and EEG during wakefulness and sleep normalized by 14months of age. Over
the subsequent 3years of follow-up, no seizure recurrence occurred, and the child’s
neurodevelopment remained unaffected. The authors attributed the infant’s spasticity to theophylline toxicity, emphasizing the potential severity of seizures, particularly of the generalized tonic–clonic type, as a consequence of theophylline
overdose. Given the prognostic implications of delayed treatment for infantile
spasms and heightened arrhythmias, the authors advocate for prompt initiation of
nitrazepam therapy [307].
The Efcacy andSafety ofNitrazepam intheTreatment ofEpilepsy
Zahan etal. assessed the efcacy, tolerability, and safety of oral nitrazepam in 41
children with drug-resistant West syndrome (WS) who underwent nitrazepam therapy. Nitrazepam has emerged as a safe and viable treatment modality for children
with refractory WS, leading to the cessation of spasms and improvements in electroclinical responses in nearly half of the patients [300]. Dreifuss etal. conducted a
multicenter randomized controlled trial to compare the effectiveness and safety of
nitrazepam and adrenocorticotropic hormone in treating infantile spasms. The study
enrolled 52 patients in a 4-week, randomized, multicenter trial, with 48 patients
under 2years of age undergoing assessment for drug efcacy. The research revealed
a statistically signicant reduction in spasm frequency with both treatments compared to baseline, although there was no signicant difference between the two
treatments. The incidence of side effects was similar in both groups, but adverse
effects were more severe in patients treated with adrenocorticotropic hormone,
leading to treatment discontinuation in six patients. The authors noted that the study
duration was insufcient to assess the long-term impact of either treatment on the
developmental status of patients [308].
Evidence-Based Medical Research onNitrazepam
Song etal. conducted a systematic review of the literature from the past decade
to outline current treatments for infantile spasms. Their ndings indicate that
topiramate, levetiracetam, zonisamide, and sodium valproate, along with benzodiazepines such as clonazepam or nitrazepam, show promise in treating West
syndrome. Other effective treatments include adrenocorticotropic hormone, steroids, vigabatrin, and dietary interventions such as a ketogenic diet and a modied Atkins diet [309].
Effect ofNitrazepam onEEG andCognitive Function
Saarelainen etal. investigated the incidence of benzodiazepines and related drugs
(BZDR) in patients with Alzheimer’s disease (AD) compared to non-AD patients
over a 5-year follow-up period. They found that BZDR use was greater in AD
2 Antiseizure Medications
147
patients than in control patients, peaking at 6months after diagnosis and remaining
signicantly elevated up to 3 years postdiagnosis. BZDRs are associated with
impaired cognitive function, which may complicate monitoring of treatment effects
in AD patients [310].
Effect ofNitrazepam Addition onPatient Quality ofLife
Jan etal. investigated the anticonvulsant properties of nitrazepam in 31 children
exhibiting various seizure patterns. Their ndings suggest that nitrazepam is a
relatively safe and efcacious medication for managing mild motor spasms, particularly infantile spasms, and may even be more benecial than adrenocorticotropic hormone therapy in this specic epilepsy subtype. In older children,
nitrazepam demonstrates utility primarily for myoclonic seizures; however, its
effectiveness appears to be constrained in terms of both its scope and duration [311].
Side Effects ofNitrazepam
Kagota etal. assessed the direct vasodilatory effects of benzodiazepines (BZDs)
and nonbenzodiazepines (non-BZDs). Zolpidem and tandospirone induced more
than 80% relaxation at a concentration of 10μM, while diazepam, etizolam, etizolam, and toxosone caused 60–70% relaxation. However, 18 other BZDs, including alprazolam, clonazepam, nitrazepam, and triazolam, along with zaleplon,
exhibited less than 50% relaxation. Additionally, the decrease in blood pressure
observed in patients taking BZDs or non-BZDs may be attributed in part to direct
vasodilation [312]. Iqbal etal. conducted a population-based longitudinal case–control study to explore the association between benzodiazepine use and cancer risk in
individuals over 20years old. BZDs are categorized into safe and unsafe groups
based on their carcinogenicity. Among the BZDs examined, diazepam, chlordiazepoxide, mezepam, nitrazepam, and oxazepam were deemed safer. However, clonazepam was associated with a greater risk of cancer. In addition, the risk of specic
cancers associated with BZD use was signicantly increased by 98% in the brain,
25% in colorectal cancer, and 10% in the lungs compared to non-BZD use.
Diazepam, chlorodiazole epoxide, medazepam, nitrazepam, and oxazepam are safe
for the treatment of cancer [313]. Dennis etal. conducted a case record study involving 90 children with tuberous sclerosis complexes. Among the 86 children with
seizures, there was a signicant association between walking impairment at 5years
of age and early seizures along with nitrazepam treatment. Signicantly more children who were unable to walk were taking nitrazepam, indicating potential adverse
effects on motor and cognitive development in disabled children [314]. Lim etal.
utilized nitrazepam to manage drug-resistant myoclonic epilepsy in 38 children.
The authors speculate that caution must be exercised when using nitrazepam and
suggest that esophageal manometry may be benecial in identifying patients at
148
W. Jing et al.
greater risk of sudden death. Oral motor dysfunction, particularly in the presence of
signicant neurological decits, may increase the likelihood of severe nitrazepam
side effects. The authors recommended conducting routine baseline esophageal
manometry and titrating anticonvulsants before initiating pharmacological intervention to mitigate esophageal spasm and minimize respiratory complications associated with nitrazepam or other benzodiazepines [315].
Basic Research onNitrazepam
Zhao etal. devised a novel animal model of epilepsy to investigate behavioral
alterations, electrocorticogram (ECoG) patterns, and the effects of ve classic
anticonvulsant drugs. Among these drugs, phenobarbital (30mg/kg) and nitrazepam (3mg/kg) completely suppressed seizures, while CBZ showed moderate
efcacy. Phenytoin and sodium valproate exhibited limited effectiveness.
Despite complete seizure suppression with phenobarbital sodium and nitrazepam, no improvement in mortality within the rst 48h was observed compared
to that in untreated rats. CBZ antagonized 60% of seizures, with the treated
mice displaying improved mobility and feeding behavior and a seemingly longer lifespan than those in the other groups. Valproate failed to suppress seizures
or reduce mortality. Additionally, another study revealed that 30mg/kg phenytoin could counteract zinc-induced seizures in rabbits [316].
Other Studies
Liao etal. conducted an analysis examining the correlation between various types
of hypnotics and the risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD), aiming to elucidate the potential association between hypnotic drug
usage and CKD risk, as well as the progression of CKD to ESRD, necessitating
dialysis. Their study revealed that the use of sleeping pills was linked to an elevated
risk of CKD after adjusting for underlying comorbidities. With the exception of
hyperlipidemia, most comorbid conditions were associated with a heightened CKD
risk. Furthermore, continuous use of hypnotic drugs following a CKD diagnosis
heightened the risk of concurrent ESRD.Subgroup analysis focusing on sleeping
pill use revealed signicant associations with increased CKD risk for several hypnotic drugs, including brotizolam, chlordiazepoxide, clonazepam, diazepam,
diimidazole, etizolam, udiazepam, unitrazepam, nitrazepam, trazodone, zolpidem, and zopiclone [317]. Kassie et al. compared the utilization of anxiolytics,
sedatives, hypnotics, opioid analgesics, and antidepressants in hip or knee surgery
patients without postoperative delirium. Their ndings indicated that preoperative
benzodiazepine reduction planning may mitigate postoperative psychosis risk.
Medications with notable precipitating risks, such as antidepressants and nitrazepam, should be temporarily discontinued or substituted with safer alternatives in
older surgical patients to minimize adverse outcomes [318].
2 Antiseizure Medications
2.1.2 Second-Generation Antiseizure Drugs
2.1.2.1 Lamotrigine
General Characteristics
[Chemical name] 3,5-Diamino-5,6-(2,3-dichlorophenyl)-1,2,4-triazine
[Structure formula]
149
[Molecular formula] C9H7N5Cl
2
[Molecular weight] 256.09
[Indications]
• Monotherapy for simple partial seizures, complex partial seizures, and primary
and secondary generalized tonic–clonic seizures in children older than 12years
and adults.
• Adjunctive therapy for simple partial seizures, complex partial seizures, and pri-
mary and secondary generalized tonic–clonic seizures in children older than
2years and adults.
• It is also indicated for the treatment of epileptic seizures associated with Lennox–
Gastaut syndrome.
[Dosage form]
Film-coated tablets: 50mg
Dispersible tablets: 5mg, 50mg
[Dosage and administration]
For monotherapy in patients over the age of 12, the initial dose is 25mg once daily
for 2weeks or 12.5mg twice daily for 2weeks; then, the dose is increased to 50mg
once daily or 25mg twice daily for another 2weeks. After this period, the dose may
be increased every 1–2weeks by a maximum of 50–100mg until the optimal therapeutic effect is achieved. The usual maintenance dose is 100–200mg/day, administered either once daily or twice a day.