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Signal Transduction and Targeted Therapy Dec 2023Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to...
Amyotrophic lateral sclerosis (ALS) is a devastating fatal neurodegenerative disease with no cure. Receptor-interacting protein kinase 1 (RIPK1) has been proposed to mediate pathogenesis of ALS. Primidone has been identified as an old drug that can also inhibit RIPK1 kinase. We conducted a drug-repurposing biomarker study of primidone as a RIPK1 inhibitor using SOD1 mice and ALS patients. SOD1 mice treated with primidone showed significant delay of symptomatic onset and improved motor performance. One-hundred-sixty-two ALS participants dosed daily with primidone (62.5 mg) completed 24-week follow-up. A significant reduction was showed in serum levels of RIPK1 and IL-8, which were significantly higher in ALS patients than that of healthy controls (P < 0.0001). Serum RIPK1 levels were correlated positively with the severity of bulbar symptoms (P < 0.05). Our study suggests that serum levels of RIPK1 and IL-8 in peripheral can be used as clinical biomarkers for the activation of RIPK1 in central nervous system in human ALS patients. Repurposing primidone may provide a promising therapeutic strategy for ALS. The effect of primidone for the treatment of other inflammatory diseases may also be considered, since the activation of RIPK1 has been implicated in mediating a variety of inflammatory diseases including COVID-19-associated cytokine release syndrome (CRS). (ChiCTR2200060149).
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Biomarkers; Interleukin-8; Mice, Transgenic; Motor Neurons; Neurodegenerative Diseases; Primidone; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 38086800
DOI: 10.1038/s41392-023-01713-z -
Molecules (Basel, Switzerland) Nov 2023The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection...
The objective of the present report was to develop and validate a simple, selective, and reproducible high-performance liquid chromatography method with UV detection suitable for routine therapeutic drug monitoring of the most commonly used antiepileptic drugs and some of their metabolites. Simple precipitation of plasma proteins with acetonitrile was used for sample preparation. 10,11-dihydrocarbamazepine was used as an internal standard. Chromatographic separation of the analytes was achieved by gradient elution on a Phenyl-Hexyl column at 40 °C, using methanol and potassium phosphate buffer (25 mM; pH 5.1) as a mobile phase. The method was validated according to the FDA guidelines for bioanalytical method validation. It showed to be selective, accurate, precise, and linear over the concentration ranges of 1-50 mg/L for phenobarbital, phenytoin, levetiracetam, rufinamide, zonisamide, and lacosamide; 0.5-50 mg/L for lamotrigine, primidone, carbamazepine and 10-monohydroxycarbazepine; 0.2-10 mg/L for carbamazepine metabolites: 10,11-trans-dihydroxy-10,11-dihydrocarbamazepine and carbamazepine-10,11-epoxide; 0.1-10 mg/L for oxcarbazepine; 2-100 mg/L for felbamate and 3-150 mg/L for ethosuximide. The suitability of the validated method for routine therapeutic drug monitoring was confirmed by quantification of the analytes in plasma samples from patients with epilepsy on combination antiepileptic therapy.
Topics: Humans; Anticonvulsants; Chromatography, High Pressure Liquid; Drug Monitoring; Carbamazepine; Oxcarbazepine
PubMed: 38067559
DOI: 10.3390/molecules28237830 -
Journal of Water and Health Nov 2023Illegal mining has overshadowed pharmaceutical pollution even though exposure to pharmaceutical waste is high. Consumption of fish potentially polluted with...
Illegal mining has overshadowed pharmaceutical pollution even though exposure to pharmaceutical waste is high. Consumption of fish potentially polluted with pharmaceuticals from the rivers continues with little concern or potential threat it poses. In the present study, the residues of one antibiotic (Chloramphenicol), five hormones (progesterone, 17-beta Estradiol, Estrone, 17a-Ethynylestradiol, and one), three environmental contaminants (4-para-nonylphenol, 4-tert-octylphenol, and Bisphenol A), one barbiturate (Primidone) and one analgesic (Diclofenac sodium salt), were investigated from fish samples from the rivers Pra, Narkwa, and the Volta. The results show a high concentration of drugs in River Pra in comparison to those in Rivers Narkwa and Volta. The hazard quotients (HQs) for the environmental contaminants were all above 1, except Bisphenol A. Furthermore, the HQs from this study suggest that consumers of fish from any of the three rivers stand a hazard risk of Chloramphenicol (19), 17a-Ethynylestradiol (4), Estrone (1.366), Diclofenac sodium salt (3.29), Progesterone (4.598), 4-tert-octylphenol (87.2), and 4-para-nonylphenol (7.252), but negligible risk against E2 (0.687), Primidone (0.014), Testosterone (0.16), and Bisphenol A (0.642). Of the fish species studied, the highest concentration of all pharmaceuticals put together is found in Clarias gariepinus, Labeo senegalensis, and Chrysichthys nigrodigitatus in that order.
Topics: Animals; Estrone; Progesterone; Ghana; Primidone; Diclofenac; Catfishes; Pharmaceutical Preparations; Risk Assessment; Chloramphenicol; Water; Water Pollutants, Chemical; Rivers; Environmental Monitoring
PubMed: 38017600
DOI: 10.2166/wh.2023.208 -
Neuroepidemiology 2023Essential tremor (ET) is one of the most common movement disorders. Oral drugs play a crucial role in treating ET, with various available options such as propranolol,...
INTRODUCTION
Essential tremor (ET) is one of the most common movement disorders. Oral drugs play a crucial role in treating ET, with various available options such as propranolol, primidone, and topiramate. However, the medication status and related factors among Chinese ET patients are unknown yet.
METHODS
This study used the baseline data from the National Survey of Essential Tremor Plus in China cohort. ET patients with information related to medication intake were included. Medication patients were defined as patients who were taking medication at the time of the survey. We further defined recommended medication users according to Chinese guideline recommendations and clinical knowledge. We used mean and standard deviation (SD), median and interquartile range (IQR), or frequencies and percentages when appropriate for descriptive analysis. We used multivariate logistic regression analyses to explore factors related to medication intake in all ET patients and in recommended medication users.
RESULTS
Of 1,153 included ET participants, 207 (18.0%) took medication. Arotinolol (115, 55.6%) and propranolol (63, 30.4%) were the top 2 used medicines. Patients with middle school education (odds ratio 0.57, 95% confidence interval 0.39-0.83), college or higher level education (0.46, 0.28-0.76), and late-onset ET (LO-ET) (0.38, 0.23-0.63) were less likely to take medication. Patients with intention tremor (1.90, 1.38-2.62), every 10-unit increase in age (1.10, 1.00-1.21), Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) Part 1 (1.63, 1.37-1.93), and TETRAS Part 2 (1.81, 1.48-2.22) were more likely to take medication. Among 332 recommended medication users, only 104 (31.3%) took medicine. The associations of LO-ET (0.36, 0.17-0.75), intention tremor (2.27, 1.35-3.81), TETRAS Part 1 (1.52, 1.09-2.13), and TETRAS Part 2 (1.59, 1.15-2.20) with medication were similar to all ET patients.
CONCLUSION
The proportion of medication intake is low among both all ET patients and recommended medication users. The top 2 commonly used medications among all ET patients are arotinolol and propranolol. Influencing factors of medication intake are different between all ET patients and recommended medication users. Clinicians are suggested to provide counseling and education on ET medication to promote medication intake.
PubMed: 37586340
DOI: 10.1159/000533171 -
Transplantation Proceedings Oct 2023Calcineurin inhibitor-related tremors occur in up to 50% of solid organ transplant recipients and are disabling in severe cases. We describe a bilateral lung transplant...
Calcineurin inhibitor-related tremors occur in up to 50% of solid organ transplant recipients and are disabling in severe cases. We describe a bilateral lung transplant recipient with essential tremors that significantly worsened after tacrolimus initiation. She did not have improvement with the change to extended-release tacrolimus, the use of everolimus as a calcineurin inhibitor-sparing agent, or the addition of primidone, clonazepam, or propranolol. She underwent magnetic resonance-guided focused ultrasound thalamotomy with significant improvement in her tremor and activities of daily living.
PubMed: 37495484
DOI: 10.1016/j.transproceed.2023.06.012 -
CNS Drugs Aug 2023Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with...
BACKGROUND
Valproate-induced encephalopathy (VIE) affects between 0.1% and 2.5% of patients under long-term epilepsy treatment. Its frequency and characteristics in adults with status epilepticus (SE) is, however, unknown.
OBJECTIVE
The aim of this study was to characterize the frequency and the clinico-biological characteristics of VIE in adult SE patients.
METHODS
We reviewed all patients included in our institutional SE registry who were treated for an SE episode between November 2021 and February 2023 and identified 39 patients who received valproate for their SE treatment. Acute VIE was defined by worsening of consciousness having led to the discontinuation of valproate, and improvement of consciousness within 96 hours after discontinuation of valproate during acute hospital treatment.
RESULTS
Patients had a mean valproate intravenous loading dose of 34.5 mg/kg and a mean maintenance dose of 15.3 mg/kg/d (1078 mg/d). Four out of 29 patients with measured ammonium had hyperammonemia. We identified four (10%) patients fulfilling acute VIE criteria. Median time from administration of valproate to the occurrence of VIE, and to resolution of VIE after cessation of valproate treatment, was 2 days for each. Three of the four VIE patients had no associated hyperammonemia. Patients who developed VIE more frequently had a history of liver disease (p = 0.023), and tended to be younger, but other clinical variables did not differ significantly from patients without VIE, including valproate loading or maintenance doses, SE cause, duration or severity, other concomitant antiseizure medications (none received topiramate, phenobarbital, or primidone).
CONCLUSION
Pending larger studies, VIE in SE seems relatively frequent and difficult to foresee; clinical alertness to symptoms is mandatory, even without hyperammonemia, and valproate withdrawal should be considered in suspected cases.
Topics: Adult; Humans; Anticonvulsants; Brain Diseases; Hyperammonemia; Status Epilepticus; Valproic Acid
PubMed: 37466895
DOI: 10.1007/s40263-023-01024-5 -
Medicines (Basel, Switzerland) Jun 2023Adverse effects of antiseizure medications (ASMs) remain one of the major causes of non-adherence. Cosmetic side effects (CSEs) are among the most commonly reported... (Review)
Review
Adverse effects of antiseizure medications (ASMs) remain one of the major causes of non-adherence. Cosmetic side effects (CSEs) are among the most commonly reported side effects of ASMs. In this context, alopecia is one of the CSEs that has a high intolerance rate leading to poor therapeutical compliance. We performed a literature review concerning alopecia as a secondary effect of ASMs. There are 1656 individuals reported with ASM-induced alopecia. Valproate (983), lamotrigine (355), and carbamazepine (225) have been extensively reported. Other ASMs associated with alopecia were cenobamate (18), levetiracetam (14), topiramate (13), lacosamide (7), vigabatrin (6), phenobarbital (5), gabapentin (5), phenytoin (4), pregabalin (4), eslicarbazepine (3), brivaracetam (2), clobazam (2), perampanel (2), trimethadione (2), rufinamide (2), zonisamide (2), primidone (1), and tiagabine (1). There were no reports of oxcarbazepine and felbamate with drug-induced alopecia. Hair loss seen with ASMs was diffuse and non-scarring. Telogen effluvium was the most common cause of alopecia. A characteristic feature was the reversibility of alopecia after ASM dose adjustment. Alopecia should be considered one important adverse effect of ASMs. Patients reporting hair loss with ASM therapy should be further investigated, and specialist consultation is recommended.
PubMed: 37367730
DOI: 10.3390/medicines10060035 -
Hospital Pharmacy Aug 2023The management of the drug-drug interaction (DDI) between primidone, a moderate to strong cytochrome P-450 (CYP) 3A4 inducer, and apixaban, a direct oral anticoagulant...
The management of the drug-drug interaction (DDI) between primidone, a moderate to strong cytochrome P-450 (CYP) 3A4 inducer, and apixaban, a direct oral anticoagulant (DOAC) and CYP3A4 substrate is complex and limited evidence exists to guide management. This case report describes a 65-year-old male, receiving primidone for essential tremor who developed an acute venous thromboembolism (VTE) requiring oral anticoagulation. DOACs are preferred over vitamin K antagonists for acute VTE treatment. Based on patient-specific variables, provider preference, and the avoidance of other DDIs, apixaban was selected. Apixaban's package insert recommends avoiding use with concomitant strong P-gp and CYP3A4 inducers due to the decreased exposure to apixaban; however, no recommendations are available for drugs that are moderate to strong CYP3A4 inducers and lack P-gp effects. Given that phenobarbital is an active metabolite of primidone, extrapolation of evidence from such literature is theoretical but provides insight into the management of this multi-faceted DDI. In the absence of the ability to monitor plasma apixaban levels, a management strategy of avoidance with a washout period of primidone based on pharmacokinetic parameters was used in this case. Additional evidence is needed to clearly understand the degree of impact and clinical significance of the DDI between apixaban and primidone.
PubMed: 37360203
DOI: 10.1177/00185787221150928 -
Future Cardiology Mar 2023Ticagrelor and aspirin is a common dual antiplatelet therapy regimen for patients who undergo percutaneous coronary intervention. Despite its ability to significantly...
Ticagrelor and aspirin is a common dual antiplatelet therapy regimen for patients who undergo percutaneous coronary intervention. Despite its ability to significantly reduce cardiovascular complications, ticagrelor response may be altered by other medications causing subtherapeutic effects. Traditionally, ticagrelor is thought to have fewer drug-drug interactions compared to other thienopyridine antiplatelet medications such as clopidogrel. Primidone, metabolized into phenobarbital, is a strong CYP-3A inducer that can reduce serum concentrations of ticagrelor resulting in ineffective antiplatelet therapy. We present a 67-year-old male who suffered in-stent thrombosis after percutaneous intervention possibly due to the interaction between primidone and ticagrelor.
Topics: Male; Humans; Aged; Ticagrelor; Platelet Aggregation Inhibitors; Primidone; Drug-Eluting Stents; Clopidogrel; Percutaneous Coronary Intervention; Acute Coronary Syndrome; Treatment Outcome
PubMed: 37313792
DOI: 10.2217/fca-2023-0011 -
Brain and Nerve = Shinkei Kenkyu No... May 2023Based on the evidence level, the first-line agents for managing essential tremors include sympathomimetic agents and primidone; however, from a tolerability standpoint,...
Based on the evidence level, the first-line agents for managing essential tremors include sympathomimetic agents and primidone; however, from a tolerability standpoint, sympathomimetic agents are the first choice. Arotinolol is the first treatment of choice because it is the only drug developed in Japan approved for treating essential tremors. If sympathomimetic agents are unavailable or ineffective, a change to primidone, or a combination of both, should be considered. Benzodiazepines and other anti-epileptic drugs should also be administered.
Topics: Humans; Primidone; Essential Tremor; Sympathomimetics; Japan; Anticonvulsants
PubMed: 37194529
DOI: 10.11477/mf.1416202376