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Chemistry & Biodiversity Jun 2024New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. The antiepileptic potential of the...
New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. The antiepileptic potential of the synthesized compounds has been tested by following standard animal screening models which include maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The study concluded that compounds 9c, 9d, 9f, 9i, 9n, and 9o possessed good antiepileptic potential when compared with standard drugs like carbamazepine and phenytoin. The results of the rotarod performance test also established them without any neurotoxicity. The motor impairment test yielded that the synthesized compounds are also good antidepressants. In-silico studies have been performed to determine the eligibility of synthesized compounds as orally administered molecules and interactions with the target proteins. The result of in-silico studies reinforced results obtained by in vivo study of the synthesized compounds along with their possible mechanism of antiepileptic action i.e. via inhibiting voltage-gated sodium channels (VGSCs) and gamma-aminobutyric acid-A receptor.
PubMed: 38822644
DOI: 10.1002/cbdv.202400642 -
Journal of Surgical Case Reports May 2024Gingival enlargement is a side effect of several different medication, including immunosuppressants, anticonvulsants, and calcium channel blockers. It is an inflammatory...
Gingival enlargement is a side effect of several different medication, including immunosuppressants, anticonvulsants, and calcium channel blockers. It is an inflammatory response that starts when plaque and calculus build up on the tooth surface. The most prevalent long-term neurological condition affecting people is epilepsy. In affluent nations, the prevalence of epilepsy is ~ 1%, whereas in less developed countries, it may >2%. The preferred medication for the condition, phenytoin, has major side effects include gingival enlargement. In addition to being visually disfiguring, this enlargement frequently affects speech, chewing and eating. Furthermore, those with poor dental hygiene, causes disabilities with motor coordination and muscular limitations leading to mental disability and physical impairments are more prone to periodontal disease. This article enlightened the mechanism of drug induced gingival enlargement clinically, microbiologically, and surgically.
PubMed: 38812578
DOI: 10.1093/jscr/rjae304 -
Skin Research and Technology : Official... Jun 2024Severe acne breakouts often lead to atrophic acne scars, which affect millions of people worldwide and can significantly affect a person's self-confidence and... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
Evaluation and comparison of the efficacy and safety of the combination of topical phenytoin and microneedling with microneedling alone in the treatment of atrophic acne scars: A controlled blinded randomized clinical trial.
INTRODUCTION
Severe acne breakouts often lead to atrophic acne scars, which affect millions of people worldwide and can significantly affect a person's self-confidence and self-image. Given the difficulty in treating atrophic acne scars, this study aims to investigate the efficacy of topical phenytoin in the treatment of atrophic acne scars.
METHOD
This split face clinical trial on 25 patients between the ages of 18 and 40 involved the application of microneedling on one side of the face, with three sessions taking place over the course of a month. On the other side, a 1% phenytoin cream was administered three times daily for 1 week following the microneedling procedure. Baseline information was collected for all patients, and follow-up assessments were conducted during the treatment sessions and 2 months after the last session. The assessments included evaluating the number and area of pores and spots, determining scar severity, assessing patient satisfaction, and recording any potential complications.
RESULTS
Among patients, 20 individuals (80%) were females, and the average age of the participants was 35.96 ± 9.23. In terms of the fine pore area, despite the fine pore count, both groups showed improvement over time (p: 0.03 vs. 0.06). Also, regarding large pore count and area, and the count and area of spots, both groups showed improvement over time (p: 0.001). However, there were no significant differences between the two groups (p > 0.05). On the other hand, when it comes to acne scar grade and patients' satisfaction, the phenytoin group outperformed the control group in all follow-up sessions and this difference was found to be significant (p: 0.001). It is worth noting that no complications were observed among any of the patients.
CONCLUSION
It appears that combining phenytoin cream with microneedling has a more effective therapeutic outcome in enhancing atrophic acne scars, when compared to microneedling alone, and this method can be regarded as a viable alternative in treating these types of scars.
Topics: Humans; Female; Phenytoin; Adult; Acne Vulgaris; Male; Cicatrix; Young Adult; Needles; Adolescent; Treatment Outcome; Patient Satisfaction; Administration, Cutaneous; Combined Modality Therapy; Atrophy; Administration, Topical; Percutaneous Collagen Induction
PubMed: 38807440
DOI: 10.1111/srt.13766 -
CNS Neuroscience & Therapeutics May 2024Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was...
AIMS
Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis-inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF.
METHODS
An intraperitoneal injection of lithium chloride-pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF.
RESULTS
Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ-H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction.
SIGNIFICANCE
SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.
Topics: Animals; Rats; Apoptosis Inducing Factor; Male; Nerve Tissue Proteins; Disease Models, Animal; Rats, Sprague-Dawley; Drug Resistant Epilepsy; Membrane Glycoproteins; Hippocampus; Anticonvulsants
PubMed: 38801174
DOI: 10.1111/cns.14778 -
Unplugging lateral fenestrations of NALCN reveals a hidden drug binding site within the pore region.Proceedings of the National Academy of... May 2024The sodium (Na) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium...
The sodium (Na) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (Nas and Cas, respectively). Unlike Nas and Cas, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145, and Y1436) that block these openings. Structural data suggest that occluded fenestrations underlie the pharmacological resistance of NALCN, but functional evidence is lacking. To test this hypothesis, we unplugged the fenestrations of NALCN by substituting the four aforementioned residues with alanine (AAAA) and compared the effects of Na, Ca, and NALCN blockers on both wild-type (WT) and AAAA channels. Most compounds behaved in a similar manner on both channels, but phenytoin and 2-aminoethoxydiphenyl borate (2-APB) elicited additional, distinct responses on AAAA channels. Further experiments using single alanine mutants revealed that phenytoin and 2-APB enter the inner cavity through distinct fenestrations, implying structural specificity to their modes of access. Using a combination of computational and functional approaches, we identified amino acid residues critical for 2-APB activity, supporting the existence of drug binding site(s) within the pore region. Intrigued by the activity of 2-APB and its analogues, we tested compounds containing the diphenylmethane/amine moiety on WT channels. We identified clinically used drugs that exhibited diverse activity, thus expanding the pharmacological toolbox for NALCN. While the low potencies of active compounds reiterate the pharmacological resistance of NALCN, our findings lay the foundation for rational drug design to develop NALCN modulators with refined properties.
Topics: Binding Sites; Humans; Phenytoin; Boron Compounds; Ion Channels; HEK293 Cells; Animals; Nerve Tissue Proteins; Membrane Proteins
PubMed: 38787877
DOI: 10.1073/pnas.2401591121 -
BioFactors (Oxford, England) May 2024Drug-induced gingival enlargement (DIGE) is a side effect of ciclosporin, calcium channel blockers, and phenytoin. DIGE is a serious disease that leads to masticatory...
Drug-induced gingival enlargement (DIGE) is a side effect of ciclosporin, calcium channel blockers, and phenytoin. DIGE is a serious disease that leads to masticatory and esthetic disorders, severe caries, and periodontitis but currently has no standard treatment. We recently reported that nuclear receptor 4A1 (NR4A1) is a potential therapeutic target for DIGE. This study aimed to evaluate the therapeutic effects of n-butylidenephthalide (BP), which increases the expression of NR4A1, on DIGE. In this study, NR4A1 mRNA expression was analyzed in the patients with periodontal disease (PD) and DIGE. We evaluated the effect of BP on NR4A1 expression in gingival fibroblasts and in a DIGE mouse model. RNA sequencing (RNA-seq) was conducted to identify the mechanisms by which BP increases NR4A1 expression. The results showed that NR4A1 mRNA expression in the patients with DIGE was significantly lower than the patients with PD. BP suppressed the upregulation of COL1A1 expression, which was upregulated by TGF-β. BP also ameliorated gingival overgrowth in DIGE mice and reduced Col1a1 and Pai1 expression. BP also decreased Il1β mRNA expression in gingival tissue in DIGE. RNA-seq results showed an increase in the expression of several genes related to mitogen-activated protein kinase including DUSP genes in gingival fibroblasts stimulated by BP. Treatment with ERK and JNK inhibitors suppressed the BP-induced increase in NR4A1 expression. In addition, BP promoted the phosphorylation of ERK in gingival fibroblasts. In conclusion, BP increases NR4A1 expression in gingival fibroblasts through ERK and JNK signaling, demonstrating its potential as a preventive and therapeutic agent against DIGE.
PubMed: 38777369
DOI: 10.1002/biof.2077 -
Cureus Apr 2024is a first-generation anticonvulsant medicine that efficiently cures a wide range of seizures, including status epilepticus, complex partial seizures, and generalized...
is a first-generation anticonvulsant medicine that efficiently cures a wide range of seizures, including status epilepticus, complex partial seizures, and generalized tonic-clonic seizures (GCTS). The major advantage of phenytoin is that its neurological functions are preserved. Phenytoin works by inhibiting voltage-dependent membrane Na channels, which are essential to generate action potential. This function inhibits the positive feedback, leading to high-frequency repeated firing, reducing seizure spread in the focal region. A purple color rash on the chest, abdomen, and trunk developed in a 21-year-old female patient after being treated with phenytoin is being reported. The presentation, pathophysiology, and management are also reviewed.
PubMed: 38774164
DOI: 10.7759/cureus.58665 -
Scientific Reports May 2024A growing body of evidence suggests that adverse drug reactions (ADRs) are a major cause of morbidity and mortality in the healthcare system. Fifteen to twenty-five... (Observational Study)
Observational Study
A growing body of evidence suggests that adverse drug reactions (ADRs) are a major cause of morbidity and mortality in the healthcare system. Fifteen to twenty-five percent of patients with epilepsy discontinued antiseizure drugs (ASDs) within 6 months of therapy owing to intolerable adverse drug reactions. In Ethiopia, the prevalence of antiseizure adverse drug reactions and associated factors was not extensively conducted in advanced settings like Jimma Medical Centers. Hence, the objective of this study is to assess patterns of adverse drug reactions and associated factors among ambulatory epileptic patients at tertiary hospitals in Ethiopia. A hospital-based prospective observational study was spanned for 1 year. Two hundred ninety patients were consecutively recruited into the study from all epileptic patients attending the ambulatory clinic. Relevant data were collected through patient interviews and medical chart reviews. The causality assessment was done by using the Naranjo Probability Scale. Epi-Data manager version 4.6.0.4 was used for data entry and statistical analysis was performed by Statistical Package for Social Science version 25.0 (SPSS). Stepwise backward logistic regression analysis was done to identify factors that increase the risk of antiseizure adverse drug reactions. The mean (± SD) age of the participants were 29.91(± 11.26) years. The overall prevalence of ADR was 33.8% (95% CI 29.2-39.9%). A total of 110 adverse drug reactions were identified among 98 patients with an average of 1.12 per patient. ADRs were frequently reported with phenobarbital (52.04%) and phenytoin (34.70%). The commonly identified adverse drug reactions were epigastric pain (27.55%) and central nervous system drowsiness (23.46%). Comorbidity (AOR = 5.91, 95% CI (2.14-16.32), seizure-free period of fewer than 2 years (AOR = 1.94, 95% CI (1.18-3.19), and polytherapy (AOR = 1.35, 95% CI (1.80-2.26) were significantly associated with adverse drug reactions. This trial had a comparatively high percentage of adverse medication reactions. Adverse medication reactions were more common in patients with polytherapy, comorbidities, and seizure-free durations less than two years. Therefore, medical practitioners should advise patients who exhibit these traits on how to reduce or avoid bad drug responses or provide comfort in the event of small incidents.
Topics: Humans; Female; Male; Anticonvulsants; Epilepsy; Adult; Prospective Studies; Ethiopia; Drug-Related Side Effects and Adverse Reactions; Adolescent; Young Adult; Middle Aged; Risk Factors; Prevalence
PubMed: 38773234
DOI: 10.1038/s41598-024-61393-9 -
Hospital Pharmacy Jun 2024Purple glove syndrome (PGS) is a rare condition characterized by limb edema, discoloration, and pain associated with intravenous and oral phenytoin administration. The...
Purple glove syndrome (PGS) is a rare condition characterized by limb edema, discoloration, and pain associated with intravenous and oral phenytoin administration. The pathophysiology is poorly understood, and there is no established treatment. Simple cases have previously been managed with hyaluronidase subcutaneous injections, with more severe cases resulting in compartment syndrome, debridement, or even amputation. In this case report, a 2-year-old boy with status epilepticus developed PGS after receiving intravenous phenytoin via a cannula on the dorsum of the right hand. The patient was successfully managed by locally infiltrating subcutaneous hyaluronidase diffusely to the affected area, titrating its dose to effect, rather than aiming to adhere to any specific dosing limitation. The child was reviewed daily by the Plastic Surgery team until being discharged, and focal lesions began to demarcate after 48 hours, with epidermal loss but no deeper trauma. The epidermis peeled within one month, with healthy underlying skin found underlying when followed up in clinic. This case illustrates that subcutaneous administration of hyaluronidase and titrating to effect provides an effective and safe treatment for treating distal cases of early PGS in children.
PubMed: 38764997
DOI: 10.1177/00185787231224064 -
Environmental Toxicology and... Jun 2024Antiepileptic drugs, such as phenytoin, are often leaked into aquatic systems through sewage facilities due to their low metabolic rate. Fish, such as the Japanese...
Antiepileptic drugs, such as phenytoin, are often leaked into aquatic systems through sewage facilities due to their low metabolic rate. Fish, such as the Japanese medaka (Oryzias latipes), demonstrate abnormal swimming behavior such as equilibrium abnormalities, rotational behavior, and vertical swimming, when exposed to phenytoin. Therefore, it is hypothesized that predator avoidance may be hindered. This study aimed to investigate the effects of phenytoin exposure-induced behavioral abnormalities in predator avoidance in Japanese medaka. The results showed that individuals with behavioral abnormalities had a reduced ability to avoid danger. Furthermore, the fish demonstrated a delayed recognition reaction to approaching predators. Additionally, predatory fish, such as silver pike characin (Ctenolucius hujeta), were more likely to prey upon abnormal individuals. In conclusion, the fish exposed to phenytoin demonstrated behavioral changes that increased its predation risk. This study is the first to determine the effects of behavioral abnormalities in Japanese medaka which was induced after phenytoin exposure on predator risk avoidance.
Topics: Animals; Phenytoin; Oryzias; Anticonvulsants; Water Pollutants, Chemical; Behavior, Animal; Predatory Behavior; Avoidance Learning
PubMed: 38763435
DOI: 10.1016/j.etap.2024.104474