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Nan Li etal. [100] conducted a study to investigate the characteristics of elderly
patients with epilepsy in rural northeast China. They examined patients with convulsive epilepsy (471 patients aged >60years) from seven counties of Jilin Province,
Northeast China, between January 2010 and December 2019. Among these, 329
patients were categorized into the early-onset epilepsy group, and 142 patients were
categorized into the late-onset epilepsy group. They found that elderly patients with
epilepsy responded well to PB monotherapy, and the difference was similar between
the two groups (p>0.05).
Yusuf Cem Kaplan etal. [101] conducted a review to assess the possible risks
of four traditional ASMs, phenytoin (PHT), PB, CBZ, and VPA, during pregnancy and lactation in comparison with two newer ASMs commonly used and
provided a discussion on the safety of antiepileptic drug use during breastfeeding. A recent analysis from the EURAP registry reported a 6.5% severe malformation rate for PB use during breastfeeding [102]. According to a meta-analysis,
PB exposure in utero signicantly increased the incidence of major congenital
malformations [103]. Severe cases of drowsiness have been reported in infants
whose mothers used PB during breastfeeding [104]. Due to the high relative
infant dose (RID) and relatively frequent adverse reactions in infants, the
American Academy of Pediatrics has categorized PB as a medication to be used
cautiously during breastfeeding [105]. Currently, these ASMs should be administered at the lowest effective dose to ensure optimal seizure control in pregnant women.
Efcacy andSafety ofthePreferred Addition ofPhenobarbital
fortheTreatment ofEpilepsy
Deepak Sharma etal. [106] conducted a literature search through the Cochrane
Central Register of Controlled Trials and various other electronic databases to
analyze two studies that met the inclusion criteria for systematic evaluation.
Both studies showed that levetiracetam is safer than PB for treating neonatal
seizures. Although PB has traditionally been used as a rst-line ASMs for seizures, concerns have arisen regarding its impact on neuronal cell apoptosis in
the developing brain. The literature has shown better seizure control after a
single loading dose of levetiracetam than after a single dose of PB, with a greater
24-h seizure cessation rate and fewer side effects. A randomized controlled trial
by Gummalla Gyandeep etal. [107] reached the same conclusion. Levetiracetam
is as effective as PB in stopping clinical seizures in premature infants, with
fewer adverse reactions. A randomized, double-blinded, parallel-group phase
III study [108] aimed to evaluate the efcacy of PB sodium injections in participants with clinical seizures. This study was designed to demonstrate the effectiveness of PB in preventing subsequent seizures and to demonstrate better
efcacy when it is used at a high dose (40mg/kg) than at a low dose (20mg/kg).
International surveys of neonatologists worldwide have indicated that PB (used
in up to 70% of cases) can serve as a rst-line ASMs, irrespective of seizure
etiology or gestational age [109].
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91
Evidence-Based Medical Research onPhenobarbital
Jogender Kumar etal. [110] conducted a systematic review and meta-analysis to
assess and compare the efcacy and safety of PB with those of other drugs used as
rst-line medications for the treatment of neonatal seizures. A total of 443 records
were screened, and nine eligible studies (719 patients) were identied. Their analysis revealed that PB demonstrated comparable effectiveness and safety to drugs
such as phenytoin sodium and levetiracetam. However, the absence of data on longterm neurodevelopmental outcomes suggests that a drug that could replace PB as a
rst-line medication for antiepileptic seizures in neonates is not yet available.
Claudio Liguori etal. [111] conducted a comprehensive literature review focusing on 25 ASMs to investigate their impact on sleep architecture and daytime sleepiness among individuals with epilepsy. In the initial study, sleep log data from 184
children with febrile convulsions were analyzed and compared with those of children treated with either placebo or PB.No signicant difference in total sleep time
was observed between the two groups. Subsequently, in a study involving 150 epilepsy patients, a higher prevalence of PB usage was noted among those experiencing excessive daytime sleepiness, suggesting a potential stimulatory effect of PB on
daytime somnolence. Another study employing multiple linear regression analysis
revealed a weak positive correlation between Pittsburgh Sleep Quality Index scores
and PB usage. Taking all factors into account, the authors concluded that PB was
associated with poor sleep quality in patients with epilepsy, but the explanation was
limited. Overall, PB did not affect or worsen sleep parameters.
Basic Research onPhenobarbital
Marie Johne etal. [112] sought to assess whether higher doses (10 mg/kg) of
bumetanide could potentiate the effects of PB in a novel rat model of birth
asphyxia. A novel neonatal seizure model was established by inducing intermittent asphyxia with 9% and 5% O2 for 30min (three 7+3min cycles) in postnatal
day 11 (P11) male and female rat pups, respectively, at a constant 20% CO2.
Contrary to expectations, bumetanide (10mg/kg) did not augment the effect of PB
(15mg/kg) on the seizure rate. PB in combination with the ester predrug N,Ndimethylaminoethyl ester (DIMAEB) or bumipramine, a predrug of bumetanide,
inhibited neonatal seizures. The bumetanide/phenobarbital combination also prevented asphyxia and postictal hippocampal neurodegenerative changes. Both
bumipramine and DIMAEB are promising tools that may help in the development
of more effective lead compounds for subsequent clinical trials. In addition, they
evaluated the effect of bumetanide/phenobarbital combination treatment on a
novel rat model of birth asphyxia (also using P11 rat pups) in another study [113].
They found that when 30mg/kgPB was applied before asphyxia instead of 15mg/
kgPB, seizures were signicantly prevented. In contrast, bumetanide (0.3mg/kg)
alone or in combination with PB (15 or 30mg/kg) had no signicant effect on
seizures. They concluded that bumetanide does not enhance the efcacy of PB in
this model.
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Side Effects ofPhenobarbital
The incidence of PB-related adverse reactions was 47%, with sedation and ataxia
being the most frequent. These reactions typically manifested within the initial
month of treatment and were temporary. Notably, higher initial doses of PB and the
introduction of a second ASM were signicantly linked to adverse reactions [114].
PB, the oldest ASM currently in widespread use, was developed in 1912 as a shortacting barbiturate. Numerous studies have provided substantial evidence indicating its
correlation with various cognitive impairments in children and adolescents. Specically,
memory function tends to be notably affected, often resulting in inferior cognitive performance compared to alternative antiepileptic medications. Jia Liu etal. [115] reported
that while there were no signicant differences in seizure severity, reductions in number
of seizures by 50% or more, or adverse events among levetiracetam (LEV), PB, and
lamotrigine (LTG), PB had a detrimental impact on cognitive abilities and mood. Frank
M.C. Besag etal. [78] extensively reviewed the literature on PubMed and concluded
that PB is particularly linked to cognitive dysfunction, encompassing memory lapses,
attention decits, and comprehension difculties. Longitudinal studies have consistently shown persistent cognitive impairments even months after the discontinuation of
PB.Thus, collective evidence underscores the signicant negative cognitive repercussions associated with PB treatment in pediatric patients.
Marta Karaźniewicz-Łada etal. [116] integrated recent literature from PubMed
and Google Base to offer insights into ASMs and their interactions with other medications, nutrients, and foods. Notably, as an inducer of ASMs, PB increases the
metabolism of oral contraceptives, thereby diminishing their therapeutic efcacy.
Additionally, compared to lamotrigine or levetiracetam, PB is associated with
increased teratogenicity and neurocognitive decits. Furthermore, PB treatment
may accelerate vitamin D metabolism in the liver, potentially leading to vitamin D
deciency. James Peters etal. [117] studied convulsions induced by ASMs using
data from PubMed, Medline, and the Cochrane Library. Examining 43 cases of
ASM-induced convulsions from 1984 to 2019, PB use was found to be associated
with 7 of 43 (16%) cases. Moreover, not all neuropsychiatric symptoms, either new
or exacerbated, were resolved upon discontinuation of PB, with 3 of 43 cases
strongly linked to more complex symptoms.
Phenobarbital Use inOther Diseases
PB demonstrates efcacy in depression treatment. Ahmad Shamabadi [118] conducted a literature review revealing that 120mg/dayPB, 20mg/day diazepam, and
100mg/day amitriptyline yielded comparable improvements in depression. Notably,
PB exhibits enhanced effectiveness in individuals with lower education levels and
heightened family stress. In two studies comparing the effects of PB with those of
imipramine and amitriptyline, PB was shown to be not only effective in treating
depression but also associated with fewer adverse effects.
While benzodiazepines remain the primary treatment for alcohol withdrawal
syndrome (AWS), PB serves as an alternative therapy. Treatment with PB for AWS
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patients demonstrated similar outcomes in terms of intubation rates, ICU lengths of
stay, and hospital stays compared to benzodiazepine treatment. However, more
robust trials are warranted to validate these ndings [119]. In patients with
benzodiazepine- resistant AWS, a loading dose of PB signicantly reduced the incidence of mechanical ventilation and the need for continuous sedation compared to
intermittent low-dose administration [120]. Delayed initiation of PB treatment
appears to increase the risk of complications related to AWS [121]. PB is known to
induce expression of cytochrome P450 enzymes 3A4 and 2B6, key hepatic metabolic pathways for numerous drugs, and induces glucuronidation, a secondary metabolic pathway. Given that both PB and opioids undergo metabolism via these
pathways, their concomitant use may lead to interactions. However, the extent of
enzyme induction seems to be dose-dependent and may take days to weeks to reach
the maximum effect, potentially decreasing the plasma concentrations of both drugs
to subtherapeutic levels, thereby heightening the risk of delayed opioid withdrawal
and relapse. Moreover, owing to its long half-life, which averages 80h in adults,
PB’s potential for adverse drug interactions may persist for weeks after discontinuation. Consequently, in alcohol withdrawal programs, in which PB is increasingly
utilized, caution should be exercised to avoid its use in patients with concurrent
opioid use disorders in most instances [122].
2.1.1.5 Primidone
Drug Characteristics
[Drug characteristics] 5-Ethyl-5-phenyl-dihydro-4,6(1H,5H)-pyrimidine dione
[Chemical structure formula]
[Molecular formula] C12H14N2O2
[Molecular weight] 325.4242
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W. Jing et al.
[Indications] The effect of primidone is similar to that of phenobarbital; approxi-
mately 25% of phenobarbital is oxidized in the body, and the other portion of the
lytic phenylethylmalamide proeclampone and its metabolites have antiepileptic
effects. Clinical agents, mainly other ASMs, are ineffective for treating grand mal
seizures and psychomotor seizures and are ineffective for treating minor seizures.
Combination treatment with phenytoin sodium can enhance the curative effect.
[Specication] 0.25g
[Usage and dosage] Primidone is started at a dose of 0.15g and gradually increased
to 0.2g, three times a day. The maximum 1day dose is 2g. Children should take
12.5–25mg/kg daily, divided two to three times.
[Adverse reactions]
Central nervous system side effects include drowsiness, nausea, vomiting, personality
changes, dizziness, ataxia, diplopia, and optic neuritis. The adverse effects on the
blood system include folate deciency, megaloblastic anemia, neonatal hemorrhage,
leukopenia, and thrombocytopenia. The skin presents with maculopapulosis and bullous dermatitis. Adverse reactions of the skeletal system include osteoporosis and
rickets. There have also been reports of systemic edema due to liver and kidney damage, as well as other syndromes such as lupus erythematosus and malignant lymphoma. The main side effects are sleepiness, personality changes, and folate deciency.
Approximately 10% of patients stopped taking the drug due to severe toxic reactions.
Clinical Application andBasic Research
History ofPrimidone
In 1953, R HANDLEY rst described primidone as a novel antiepileptic agent [123].
In 1954, S GOLDIN described the toxic effects of primidone [124]. In 1954, P W
NATHAN et al. discovered primidone for the treatment of nonidiopathic epilepsy
[125]. In 1955, V.SCARINCI discovered the pharmacological effects of primidone
[126]. In 2005, M Lopez-Gomez etal. reported that primidone was associated with
interseizure depression in patients with epilepsy [127]. In 2021, Abhishek Lenka etal.
reported that primidone intolerance in essential tremor patients was not just an agerelated issue [128]. Primidone is a recognized narrow therapeutic index drug (NTID)
and is included in the NTID catalog in China, the United States, and Japan. Its efcacy
was described by Desilvey in 1980, with subsequent conrmation of its safety and
effectiveness in treating epileptic seizures, supported by four cases reported in China.
Primidone intheTreatment ofEpilepsy
An observational study of primidone in the treatment of epilepsy revealed that partial persistent epilepsy, often associated with cerebral cortex lesions, may also stem
from subcortical lesions. Trevor etal. described a patient with partial persistent
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epilepsy who was unresponsive to conventional anticonvulsants but had a signicant brief response to alcohol, followed by a response to primidone. This response
pattern, akin to that observed in essential tremors, suggests a shared pathology
within the same anatomical network. Consequently, a novel pathophysiological
model is proposed to explain the development of persistent partial epilepsy in both
cortical and subcortical disease processes [129]. To evaluate the concentration of
antiseizure medications (ASMs) in the breast milk of women with epilepsy (WWE)
during lactation, Ramzi etal. integrated data on estimated daily intake (EDI) and
relative infant dose (RID) of ASMs, assessing potential risks to infants. Across the
15 included studies, ASM levels in breast milk were reported, with varying RIDs for
different medications. The RIDs of CBZ, lamotrigine, primidone, phenobarbital,
gabapentin, valproic acid, ethosuximide, levetiracetam, and topiramate were 3.70%,
36.33%, 4.96%, 3.15%, 4.37%, 1.90%, 31.49%, 12.50%, and 12.18%, respectively.
Breastfeeding may be restricted or even stopped when adverse signs of excessive
sedation/lethargy and/or weight gain occur in infants exposed to primidone and
phenobarbital, ethosuximide/primidone, or ethosuximide/phenobarbital. It was concluded that ASMs can be detected in the breast milk of WWE and in the plasma/
serum of infants exposed to breast milk. Healthcare providers and WWE may use
the results of this study to make informed decisions about the safety of breastfeeding when taking ASMs. Approximately 70% of individuals with epilepsy can
achieve seizure freedom with proper treatment. Discontinuing ASMs when seizures
are controlled can mitigate side effects but may increase the risk of recurrence [74].
Jingjing Wang etal. compared the recurrence rates among patients who continued
ASMs therapy against those who stopped it. Nevertheless, it remains uncertain
whether discontinuing ASMs is correlated with increased seizure recurrence. The
primary aim of this meta-analysis was to determine whether there was a discrepancy
in epilepsy recurrence rates between seizure-free patients who maintained ASMs
usage and those who stopped it. The heterogeneity was assessed via the I2 value,
and odds ratios (ORs) and 95% condence intervals (CIs) were calculated using the
Mantel–Haenszel test; seven cohort studies and randomized controlled trials (RCTs)
meeting the inclusion criteria were included. The quality of the studies was evaluated with the Newcastle–Ottawa Scale and the Jadad Scale. Their analysis included
1253 patients, revealing a greater recurrence rate among patients who discontinued
ASMs than among those who continued therapy. Furthermore, they investigated
seizure recurrence rates postdiscontinuation among seizure-free patients treated
with various ASMs (CBZ, phenytoin, valproate, and phenobarbital/primidone),
incorporating four studies totaling 625 patients. No signicant differences in epilepsy recurrence rates were observed among the different ASMs treatment regimens
[130]. Inhalation of hyperbaric oxygen can potentially induce seizures akin to epilepsy. Hence, Ivan T etal. conducted experiments to investigate whether pretreatment with an FDA-approved antiepileptic medication could mitigate seizures in a
hyperoxic setting with an absolute concentration of 5 atmospheres. Drugs were chosen from two anticipated functional categories: Na+ channel blockers and GABA
enhancers. Among the ve sodium channel blockers tested, CBZ and lamotrigine
exhibited seizure latencies three times greater than those of the solvent control
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W. Jing et al.
group. However, the effectiveness of primidone, zonisamide, and oxazepane was
limited. As these crucial elements of neuronal excitation and inhibition are implicated in the development of various epileptic conditions, including generalized epilepsy, the authors suggest that common pathways might be involved in these
pathological processes despite initial divergent damage. Moreover, it remains
unclear whether prolonged exposure to high levels of oxygen triggers spontaneous
recurrent seizures, a hallmark of clinical epilepsy. Nonetheless, research on hyperbaric oxygen toxicity can shed light on new molecular mechanisms underlying epileptic seizures of diverse origins. Additionally, the neuropathology associated with
hyperbaric oxygen exposure lends credence to the hypothesis proposed by some
researchers that oxidative stress plays a pivotal role in the onset of clinical epilepsy [131].
Evidence-Based Medical Research onPrimidone
Therapeutic drug monitoring (TDM) is crucial for optimizing and tailoring the
treatment of ASMs, particularly in vulnerable groups such as pregnant women,
elderly individuals, and children. However, the practical application of TDM often
faces challenges due to limitations in blood collection methods. Thus, Thierry etal.
investigated a novel home sampling technique known as volumetric absorption microsampling (VAMS). Their study aimed to assess VAMS by analyzing and quantifying the concentrations of 16 different ASMs in whole blood samples. Venous blood
samples were obtained from 138 patients at the Kempenhaeghe Epilepsy Academic
Center. The concentrations of ASMs were measured using both the VAMS method
(whole blood) and the conventional method (serum). Additionally, the impact of
hematocrit on recovery was evaluated. This study also examined the stability of
ASMs in microsampling devices over time and the inuence of temperature on their
stability using ASMs-infused blood. The results indicated that VAMS could accurately detect 16 different ASMs within a 2-day period. When the recovery deviation
was less than 10%, VAMS showed a strong correlation with conventional sampling.
Furthermore, hematocrit levels between 0.3 and 0.5 (L/L) did not affect the results.
While the storage temperature had an impact on the stability of some ASMs in
VAMS, the majority of samples remained unaffected. Conclusion: VAMS can accurately detect multiple ASMs within 2days [132].
Effect ofPrimidone Addition onPatient Quality ofLife
To characterize the clinical presentation, progression, and management of essential
tremor (ET) in children, Debabrata etal. conducted a retrospective analysis of clinical data spanning 27years from 1984 to 2011. The study included 211 children with
ET, comprising 130 males and 81 females. Seven children (14.09±5.0years) were
included, and the age of onset was 9.71±5.62years. The majority of patients (199)
exhibited bilateral hand tremors, with others presenting with asymmetrical or unilateral tremors that later became bilateral. Additional manifestations included leg
tremors, head tremors, trunk tremors, and resting tremors. A family history of ET
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was reported in 35% of patients, predominantly involving parents and siblings.
Functional impairments were observed in 55% of patients, affecting activities such
as writing, eating, and playing musical instruments. Treatment strategies included
propranolol, atenolol, primidone, metoprolol, and nadolol. Follow-up data from 99
patients over an average period of 1.82±2.21years revealed that untreated tremors
remained stable in some patients, while propranolol treatment led to signicant
short-term improvement in 15 of 20 patients. Overall, this study represents the largest case series of ET in children to date, highlighting the potential for onset at birth,
lower familial predisposition compared to adults, and the prevalence of functional
disabilities requiring medication in a substantial proportion of cases [133]. Gene
expression analysis has been shown to be highly effective in predicting drug
responses in cell models, as demonstrated by an endeavor by Charles-Etienne etal.
to apply this method in the context of essential tremor (ET), a condition in which
many patients respond to two drugs: propranolol and primidone. In this study, cerebellar DAOYs and neural progenitor cells were treated with clinical concentrations
of propranolol and primidone for 5 days. Subsequently, RNA sequencing was
employed to pinpoint differentially expressed genes that converged during the treatment process. Propranolol was observed to inuence the expression of genes previously linked to ET and other movement disorders, including TRAPPC11. Pathway
enrichment analysis of these targeted genes revealed multiple terms associated with
calcium signaling, endosome sorting, axon guidance, and neuronal morphology.
Moreover, the genes affected by ET drugs exhibited enrichment in cell types
expressing ET-related genes prominently in cortical and cerebellar tissues.
Collectively, these ndings shed light on potential cellular and molecular mechanisms linked to tremor alleviation and pinpoint relevant genetic biomarkers for
assessing ET drug responsiveness [134].
Side Effects ofPrimidone
Abhishek et al. proposed that there are limited options available. Among them,
primidone stands out as one of only two primary drugs, but it is associated with
signicant adverse reactions. The reasons why some essential tremor patients using
primidone experience adverse reactions while others do not remain unclear, especially considering that these reactions seem to be more common in essential tremor
patients than in those with epilepsy who are treated with primidone. Although direct
comparative data are lacking, an examination of prior studies involving essential
tremor and epilepsy patients suggested that primidone tends to be better tolerated in
the former. Moreover, not all essential tremor patients experience adverse reactions
of a similar nature or severity. The discussion delves into several potential mechanisms underlying this variability in primidone intolerance, including older age (in
both essential tremor and epilepsy patients), potential cross-tolerance in epilepsy
patients, and neurobiological abnormalities related to GABA in essential tremor
patients [128].
To characterize the clinical manifestations of adverse skin reactions and
cross- reactivities induced by antiepileptic medications and to contrast the usage
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patterns of these drugs among epileptic patients with and without a history of
rash, Tallulah et al. conducted an analysis involving patients who developed
rashes within 12weeks of commencing antiepileptic therapy. The occurrence of
rash was corroborated through medical records, interviews, and patient identication of lesions via visual aids. The minimum follow-up period was 8months.
The control cohort comprised epileptic individuals who had consistently been
taking ASMs for at least 12weeks without experiencing any rash. A total of 109
patients and 99 controls were enrolled. The ndings revealed that cross-reactivity was more prevalent among patients with a history of Stevens-Johnson syndrome (29%) and Stevens-Johnson syndrome/toxic epidermal necrolysis overlap
(50%) (p=0.01). While most rashes were mild, the utilization pattern of ASMs
differed from that of the control group, with a lower utilization rate of drugs
typically associated with severe adverse skin reactions (e.g., CBZ, phenytoin,
phenobarbital, primidone, oxcarbazepine, and lamotrigine) (p < 0.001).
However, cross-sensitization was not prevalent among patients exposed to highrisk drugs. A history of cutaneous adverse reactions could inuence the selection of antiepileptic medications. Cross-sensitivity was more frequent in severe
cases, yet most patients exhibited mild, self-limiting rashes. Future investigations should explore the signicance of mild rashes in managing lifelong epilepsy [135].
Laboratory Studies ofPrimidone
The transient receptor potential (TRP) channel TRPM3, associated with the
melastatin family, functions as a nonselective cation channel present in neurons
prone to injury and activated by heat. Given that TRPM3-decient mice exhibit
inammatory thermal hyperalgesia, inhibiting TRPM3 expression with drugs
may confer antinociceptive effects. To identify TRPM3 inhibitors, uorescence
calcium inux assays and screening libraries containing approved or clinically
tested drugs were utilized. The biophysical characteristics of channel inhibition
were assessed using electrophysiological methods. Diclofenac, a nonsteroidal
anti-inammatory drug; maprotiline, a tetracyclic antidepressant; and primidone, an anticonvulsant, have emerged as highly potent TRPM3 blockers with
semimaximum inhibition at concentrations ranging from 0.6 to 6μM and notable specicity for TRPM3. In particular, primidone exhibited biological activity, effectively inhibiting TRPM3 activation induced by pregnenolone sulfate
(PregS) and heat at concentrations signicantly lower than the plasma levels
typically used in antiepileptic therapy. Primidone inhibited PregS-induced calcium inux through TRPM3 via variable structure regulation and reversed the
atypical inward rectier TRPM3 current caused by the combined action of
PregS and clotrimazole. In vivo experiments conducted by Ute etal. revealed
the analgesic effects of low-dose primidone using PregS and a heat-induced
mouse model of pain, including inammatory hyperalgesia [136]. The solidphase FTIR and FT-Raman spectra of primidone were captured within the spectral ranges of 4000–400cm(−1) and 4000–100cm(−1), respectively. Following
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the acquisition, the vibration spectrum underwent thorough analysis, with
assignments made and further examination conducted on the underlying principles. The experimental wavenumbers were juxtaposed with their theoretically
standardized counterparts determined through DFT.Raman strength was gauged
using the B3LYP/6-31G(d,p) method. Furthermore, the B3LYP/6-311++G(d,p)
method was employed to determine the total molecular electron density and
molecular electrostatic potential surface, revealing the distribution of the electrostatic potential encompassing both electrons and nuclei. The HOMO and
LUMO energies were quantied, while the analysis of the natural bond orbitals
of primidone indicated the presence of intramolecular charge transfer.
Additionally, (1)H and (13)C NMR spectra were recorded, facilitating the computation of chemical shifts for the molecules [137].
Basic Research onPrimidone
Theresa etal. investigated RIPK1 inhibitors, culminating in the proposal of an
aromatic ASM alongside the FDA-approved primidone as a potent inhibitor of
RIPK1 activation both invitro and in a mouse model of TNF-α-induced shock,
replicating the exaggerated inammatory conditions akin to cytokine release syndrome. These ndings advocate for the progression of clinical trials aimed at
evaluating the efcacy of RIPK1 inhibition in COVID-19 patients. An application
for a clinical trial utilizing primidone to treat a subset of patients with SARSCoV-2-positive acute respiratory distress syndrome is presently undergoing submission to EudraCT, the European Union Medicines Regulatory Authority
Clinical Trials Database. Given the favorable safety prole, tolerability, pharmacokinetics, and pharmacodynamics of primidone, its clinical use in treating diseases caused by pathological RIPK1 activation is straightforward. It is logical to
test other drugs that have been approved for other indications and have been marketed on a large scale [138].
Studies ofPrimidone Use forOther Conditions
Andrew etal. conducted a retrospective review of medical records encompassing all
female patients treated with primidone for primary or secondary laryngeal spasm or
essential tremor at a tertiary care center. The mean (SD) age of the 30 patients was
71.9 (11.8) years, and the average (SD) treatment duration was 5.25 (7.22) months.
Among them, 30% had concurrent dysphonia, with various diagnoses, including
spasmodic dysphonia and laryngeal reux disease. Approximately 40% had received
prior treatment. Notably, 54% reported improvement in their vocal symptoms, and
55% continued primidone therapy without discontinuation. However, adverse reactions were experienced by 73% of patients, leading to treatment cessation in a substantial portion of patients. Among those who stopped treatment, there was no
signicant difference in discontinuation rates between patients who experienced
adverse reactions and those who did not. Subsequently, 53% of patients commenced
Botox therapy, with variable clinical outcomes. Although 36% reported