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PloS One 2023The Clibadium spp. is a shrub of occurrence in the Amazon, popularly known as Cunambi. The compounds in the leaves demonstrate ichthyotoxic properties, and its major...
The Clibadium spp. is a shrub of occurrence in the Amazon, popularly known as Cunambi. The compounds in the leaves demonstrate ichthyotoxic properties, and its major substance, cunaniol, is a powerful central nervous system stimulant with proconvulsant activity. Few current studies relate behavioral changes to the electrophysiological profile of fish poisoning. This study aimed to describe the behavioral, electromyographic, electroencephalographic, electrocardiographic, and seizure control characteristics of anticonvulsant drugs in Colossoma macropomum submitted to cunaniol intoxication during bathing containing 0.3 μg/L cunaniol. The behavioral test showed rapid evolution presenting excitability and spasms, which were confirmed by the analysis of Electroencephalogram (EEG), Electromyogram (EMG), and changes in cardiac function detected in the ECG. Cunaniol-induced excitability control was evaluated using three anticonvulsant agents: Phenytoin, Phenobarbital, and Diazepam. While phenytoin was not effective in seizure control, diazepam proved to be the most efficient. These results demonstrate the susceptibility of Colossoma macropomum to cunaniol poisoning, given that the central nervous system and electrocardiographic changes were considered severe.
Topics: Animals; Electrocorticography; Electroencephalography; Characiformes; Anticonvulsants; Diazepam
PubMed: 37390086
DOI: 10.1371/journal.pone.0287681 -
Pharmaceuticals (Basel, Switzerland) Jul 2023Antibiotic resistance is a global problem and bacterial biofilms contribute to its development. In this context, this study aimed to perform the synthesis and...
Antibiotic resistance is a global problem and bacterial biofilms contribute to its development. In this context, this study aimed to perform the synthesis and characterization of seven materials based on silica mesoporous nanoparticles functionalized with three types of fluoroquinolones, along with Cu or Ag species to evaluate the antibacterial properties against , , , and , including clinical and multi-drug-resistant strains of and . In addition, in order to obtain an effective material to promote wound healing, a well-known proliferative agent, phenytoin sodium, was adsorbed onto one of the silver-functionalized materials. Furthermore, biofilm studies and the generation of reactive oxygen species (ROS) were also carried out to determine the antibacterial potential of the synthesized materials. In this sense, the Cu materials showed antibacterial activity against and , potentially due to increased ROS generation (up to 3 times), whereas the Ag materials exhibited a broader spectrum of activity, even inhibiting clinical strains of MRSA and In particular, the Ag material with phenytoin sodium showed the ability to reduce biofilm development by up to 55% and inhibit bacterial growth in a "wound-like medium" by up to 89.33%.
PubMed: 37513873
DOI: 10.3390/ph16070961 -
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 -
Biological & Pharmaceutical Bulletin Sep 2023The hepatic elimination of chemical substances in pharmacokinetic models requires hepatic intrinsic clearance (CL) parameters for unbound drug in the liver, and these...
The hepatic elimination of chemical substances in pharmacokinetic models requires hepatic intrinsic clearance (CL) parameters for unbound drug in the liver, and these are regulated by the liver-to-plasma partition coefficients (K). Both Poulin and Theil and Rodgers and Rowland have proposed in silico expressions for K for a variety of chemicals. In this study, two sets of in silico K values for 14 model substances were assessed using experimentally reported in vivo steady-state K data and time-dependent virtual internal exposures in the liver and plasma modeled by forward dosimetry in rats. The K values for 14 chemicals independently calculated using the primary Poulin and Theil method in this study were significantly correlated with those obtained using the updated Rodgers and Rowland method and with reported in vivo steady-state K data in rats. When pharmacokinetic parameters were derived based on individual in vivo time-dependent data for diazepam, phenytoin, and nicotine in rats, the modeled liver and plasma concentrations after intravenous administration of the selected substrates in rats using two sets of in silico K values were mostly similar to the reported time-dependent in vivo internal exposures. Similar results for modeled liver and plasma concentrations were observed with input parameters estimated by machine-learning systems for hexobarbital, fingolimod, and pentazocine, with no reference to experimental pharmacokinetic data. These results suggest that the output values from rat pharmacokinetic models based on in silico K values derived from the primary Poulin and Theil model would be applicable for estimating toxicokinetics or internal exposure to substances.
Topics: Rats; Animals; Tissue Distribution; Liver; Pharmaceutical Preparations; Plasma; Models, Biological
PubMed: 37380443
DOI: 10.1248/bpb.b23-00371 -
International Journal of Clinical... Nov 2023Gingival enlargement or gingival overgrowth (GO) is a very common complication of the various classes of drugs and the most common being, the anticonvulsant drug...
BACKGROUND
Gingival enlargement or gingival overgrowth (GO) is a very common complication of the various classes of drugs and the most common being, the anticonvulsant drug phenytoin (PHT). PHT and its metabolites have a direct effect on the periodontal tissues; with poor oral hygiene also contributing to the severity of inflammation in patients with drug-induced gingival overgrowth (DIGO).
CASE DESCRIPTION
Here we present a case of PHT-induced gingival overgrowth (PGO) in a 12-year-old male patient and discuss the management of the condition.
CONCLUSION
Management of drug-induced overgrowth of gingiva includes strict oral hygiene maintenance practice, meticulous professional care with several adjunctive periodontal therapies like photodynamic therapy and Local drug delivery. Surgical treatment is indicated if the overgrown tissue has become fibrotic.
CLINICAL SIGNIFICANCE
The pediatric dentist plays an important role in early identification and proper management of the condition by timely intervention and collaboration with other specialists.
HOW TO CITE THIS ARTICLE
Dalal R, Garg S, Gupta A. Nonsurgical Management of Drug-induced Gingival Overgrowth in a Young Patient. Int J Clin Pediatr Dent 2023;16(S-3):S331-S334.
PubMed: 38268630
DOI: 10.5005/jp-journals-10005-2482 -
Journal of Pharmaceutical Analysis Dec 2023The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme (CYP), which plays a crucial role in...
The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme (CYP), which plays a crucial role in the metabolism of neurosteroids. The antiepileptic drug phenytoin (PHT) has been observed to induce neuronal side effects in patients, which could be attributed to its induction of CYP expression and testosterone (TES) metabolism in the hippocampus. While pregnane X receptor (PXR) is widely known for its regulatory function of CYPs in the liver, we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile (PCN), a PXR agonist, has differential effects on CYP expression in the liver and hippocampus. Specifically, the PCN treatment resulted in the induction of cytochrome P450, family 3, subfamily a, polypeptide 11 (CYP3A11), and CYP2B10 expression in the liver, while suppressing their expression in the hippocampus. Functionally, the PCN treatment protected mice from PHT-induced hippocampal nerve injury, which was accompanied by the inhibition of TES metabolism in the hippocampus. Mechanistically, we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent, rather than PXR independent, as demonstrated by genetic and pharmacological models. In conclusion, our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR. Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.
PubMed: 38223454
DOI: 10.1016/j.jpha.2023.07.013 -
Pharmaceutics Apr 2024Solid dispersions are a promising approach to enhance the dissolution of poorly water-soluble drugs. Solid crystalline formulations show a fast drug dissolution and a...
Solid dispersions are a promising approach to enhance the dissolution of poorly water-soluble drugs. Solid crystalline formulations show a fast drug dissolution and a high thermodynamic stability. To understand the mechanisms leading to the faster dissolution of solid crystalline formulations, physical mixtures of the poorly soluble drugs celecoxib, naproxen and phenytoin were investigated in the flow through cell (apparatus 4). The effect of drug load, hydrodynamics in the flow through cell and particle size reduction in co-milled physical mixtures were studied. A carrier- and drug-enabled dissolution could be distinguished. Below a certain drug load, the limit of drug load, carrier-enabled dissolution occurred, and above this value, the drug defined the dissolution rate. For a carrier-enabled behavior, the dissolution kinetics can be divided into a first fast phase, a second slow phase and a transition phase in between. This study contributes to the understanding of the dissolution mechanism in solid crystalline formulations and is thereby valuable for the process and formulation development.
PubMed: 38675170
DOI: 10.3390/pharmaceutics16040510 -
PloS One 2024This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy...
This retrospective cohort study described the obstetric and neonatal outcomes, antiseizure medication (ASM) use, and types of seizures in pregnant women with epilepsy (PWWE). Data collected from the medical records of 224 PWWE aged < 40 years with controlled or refractory seizures and 492 pregnant women without epilepsy (PWNE) control group from high-risk maternity hospitals in Alagoas between 2008 and 2021 were included in this study. The obstetric and neonatal outcomes observed in PWWE were pregnancy-related hypertension (PrH) (18.4%), oligohydramnios (10.3%), stillbirth (6.4%), vaginal bleeding (6%), preeclampsia (4.7%), and polyhydramnios (3%). There was a greater likelihood of PrH in PWWE with generalized tonic-clonic seizures (GTCS) and that of maternal intensive care unit (ICU) admissions in those with GTCS and status epilepticus, and phenytoin and lamotrigine use. PWWE with GTCS had a higher risk of stillbirth and premature delivery. PWWE with status epilepticus were treated with lamotrigine. Phenobarbital (PB) with diazepam were commonly used in GTCS and status epilepticus. Total 14% patients did not use ASM, while 50.2% used monotherapy and 35.8% used polytherapy. Total 60.9% of patients used PB and 25.2% used carbamazepine. This study described the association between the adverse obstetric and neonatal outcomes and severe seizure types in PWWE.
Topics: Infant, Newborn; Female; Humans; Pregnancy; Lamotrigine; Pregnant Women; Retrospective Studies; Stillbirth; Brazil; Anticonvulsants; Seizures; Epilepsy; Phenobarbital; Status Epilepticus
PubMed: 38558080
DOI: 10.1371/journal.pone.0291190 -
Epilepsy Research Mar 2024Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients...
Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.
Topics: Humans; Adolescent; Topiramate; Levetiracetam; Phenytoin; Retrospective Studies; Epilepsy; Insurance
PubMed: 38417192
DOI: 10.1016/j.eplepsyres.2024.107313 -
PloS One 2024Although antiseizure medications play a crucial role in the management of epilepsy, their benefit can be compromised due to drug-related problems. Drug therapy problems... (Observational Study)
Observational Study
BACKGROUND
Although antiseizure medications play a crucial role in the management of epilepsy, their benefit can be compromised due to drug-related problems. Drug therapy problems can lead to poor seizure control, reduced quality of life, and increased morbidity and mortality in patients with epilepsy. However, in our setting, there is limited knowledge about drug therapy problems and the factors that contribute to them.
OBJECTIVE
The aim of this study was to investigate the prevalence and contributing factors of drug-therapy problems among patients with epilepsy.
METHODOLOGY
A hospital-based prospective observational study was conducted at the neurologic clinic of Ayder Comprehensive Specialized Hospital, located in the Tigray region of Northern Ethiopia. The study included adult patients diagnosed with epilepsy who had been taking at least one antiseizure medication for a minimum of six months. Data were collected by conducting patient interviews and expert reviews of medical and medication records. Prior to data review and interviews, each patient provided written informed consent. Drug therapy problems were identified and classified using Cipolle's method, followed by a consensus review conducted with a panel of experts. Statistical analysis was performed using a statistical software package; SPSS version 22. Binary logistic regression analysis was conducted to determine the contributing factors of drug therapy problems. Statistical significance was determined at p<0.05.
RESULTS
A study conducted on 250 participants revealed that 55.2% of the patients experienced one or more drug therapy problems. Our analysis identified a total of 282 drug therapy problems, with a mean of 2±0.52 drug therapy problems per patient. The most commonly observed drug therapy problems were dosage too low (30.0%), noncompliance (22%), adverse drug reaction (18%), and unnecessary drug therapy (16.4%). The commonly involved antiseizure medications in these drug therapy problems were phenytoin (22.8%), Valproic acid (20.8%), and Phenobarbital (18.4%). Furthermore, our findings revealed that combination therapy (AOR: 3.92, 95%CI: 1.19-12.97) and uncontrolled seizure (AOR: 108.37, 95%CI: 38.7-303.6) exhibited significant associations with drug therapy problems.
CONCLUSION
Drug therapy problems were prevalent among patients with epilepsy. The use of combination therapy and the presence of uncontrolled seizures were identified as significant indicators of drug therapy problems. Therefore, more emphasis should be given to patients with multiple medications and uncontrolled seizures.
Topics: Adult; Humans; Quality of Life; Epilepsy; Seizures; Phenytoin; Hospitals
PubMed: 38451979
DOI: 10.1371/journal.pone.0299968