-
Pharmaceutics Oct 2023Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted...
Regulatory agencies worldwide expect that clinical pharmacokinetic drug-drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug's safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4'-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development.
PubMed: 37896246
DOI: 10.3390/pharmaceutics15102486 -
Neurocritical Care Jun 2024There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury... (Meta-Analysis)
Meta-Analysis
Guidelines for Seizure Prophylaxis in Adults Hospitalized with Moderate-Severe Traumatic Brain Injury: A Clinical Practice Guideline for Health Care Professionals from the Neurocritical Care Society.
BACKGROUND
There is practice heterogeneity in the use, type, and duration of prophylactic antiseizure medications (ASMs) in patients with moderate-severe traumatic brain injury (TBI).
METHODS
We conducted a systematic review and meta-analysis of articles assessing ASM prophylaxis in adults with moderate-severe TBI (acute radiographic findings and requiring hospitalization). The population, intervention, comparator, and outcome (PICO) questions were as follows: (1) Should ASM versus no ASM be used in patients with moderate-severe TBI and no history of clinical or electrographic seizures? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT/fPHT) be preferentially used? (3) If an ASM is used, should a long versus short (> 7 vs. ≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure, late seizure, adverse events, mortality, and functional outcomes. We used Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to generate recommendations.
RESULTS
The initial literature search yielded 1998 articles, of which 33 formed the basis of the recommendations: PICO 1: We did not detect any significant positive or negative effect of ASM compared to no ASM on the outcomes of early seizure, late seizure, adverse events, or mortality. PICO 2: We did not detect any significant positive or negative effect of PHT/fPHT compared to LEV for early seizures or mortality, though point estimates suggest fewer late seizures and fewer adverse events with LEV. PICO 3: There were no significant differences in early or late seizures with longer versus shorter ASM use, though cognitive outcomes and adverse events appear worse with protracted use.
CONCLUSIONS
Based on GRADE criteria, we suggest that ASM or no ASM may be used in patients hospitalized with moderate-severe TBI (weak recommendation, low quality of evidence). If used, we suggest LEV over PHT/fPHT (weak recommendation, very low quality of evidence) for a short duration (≤ 7 days, weak recommendation, low quality of evidence).
Topics: Humans; Brain Injuries, Traumatic; Anticonvulsants; Seizures; Levetiracetam; Critical Care; Adult; Phenytoin; Hospitalization; Practice Guidelines as Topic
PubMed: 38316735
DOI: 10.1007/s12028-023-01907-x -
Die Pharmazie Jul 2023Physiologic changes due to aging, pregnancy, nutritional status, drug interactions, and can affect pharmacokinetics and pharmacodynamics of antiepileptic drugs. In this... (Review)
Review
Physiologic changes due to aging, pregnancy, nutritional status, drug interactions, and can affect pharmacokinetics and pharmacodynamics of antiepileptic drugs. In this review article, the interactions between phenytoin and herbs recorded in the literature were summarized according to the Medline database (via PubMed). Our results revealed that, changes in phenytoin's bioavailability were reported for co-administration of herbs or herbal extracts. An increase in phenytoin blood levels was established with , Mentat, and in and/or studies. In contrast, herbphenytoin interactions led to sub-therapeutic levels of phenytoin in other cases with herbs such as Cannabis, , , , and . In addition, the findings of other pharmcodynamic experiments showed that various herbs, including , , L, and , improved the pharmacological impact of phenytoin. To reduce the patients' health risks, health professionals involved in their treatment are expected to be thoroughly educated about the interactions between phenytoin and medicinal plants.
Topics: Humans; Plants, Medicinal; Phenytoin; Anticonvulsants; Drug Interactions
PubMed: 37537774
DOI: 10.1691/ph.2023.3546 -
Frontiers in Pediatrics 2023Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved... (Review)
Review
Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam. IL-1β signal blockade with Anakinra has shown promising results in avoiding seizure recurrence and generalization in inflammatory refractory epilepsy. Inhibiting the IL-1β converting enzyme (ICE)/caspase-1 is also being investigated as a possible target for managing drug-resistant epilepsies. Targeting the ATP-P2X7R signal, which activates the NLRP3 inflammasome and triggers inflammatory molecule release, is another avenue of research. Interestingly, astaxanthin has shown promise in attenuating neuroinflammation in SE by inhibiting the ATP-P2X7R signal. Furthermore, IL-6 blockade using tocilizumab has been effective in RSE and in reducing seizures in patients with febrile infection-related epilepsy syndrome (FIRES). Other potential approaches include the ketogenic diet, which may modulate pro-inflammatory cytokine production, and the use of cannabidiol (CBD), which has demonstrated antiepileptic, neuroprotective, and anti-inflammatory properties, and targeting HMGB1-TLR4 axis. Clinical experience with anti-cytokine agents such as Anakinra and Tocilizumab in SE is currently limited, although promising. Nonetheless, Etanercept and Rituximab have shown efficacy only in specific etiologies of SE, such as autoimmune encephalitis. Overall, targeting inflammatory pathways and cytokines shows potential as an innovative therapeutic option for drug-resistant epilepsies and SE, providing the chance of directly addressing its underlying mechanisms, rather than solely focusing on symptom control.
PubMed: 38078329
DOI: 10.3389/fped.2023.1251914 -
Medicina (Kaunas, Lithuania) Feb 2024Asterixis is a subtype of negative myoclonus characterized by brief, arrhythmic lapses of sustained posture due to involuntary pauses in muscle contraction. We performed... (Review)
Review
Asterixis is a subtype of negative myoclonus characterized by brief, arrhythmic lapses of sustained posture due to involuntary pauses in muscle contraction. We performed a narrative review to characterize further asterixis regarding nomenclature, historical aspects, etiology, pathophysiology, classification, diagnosis, and treatment. Asterixis has been classically used as a synonym for negative myoclonus across the literature and in previous articles. However, it is important to distinguish asterixis from other subtypes of negative myoclonus, for example, epileptic negative myoclonus, because management could change. Asterixis is not specific to any pathophysiological process, but it is more commonly reported in hepatic encephalopathy, renal and respiratory failure, cerebrovascular diseases, as well as associated with drugs that could potentially lead to hyperammonemia, such as valproic acid, carbamazepine, and phenytoin. Asterixis is usually asymptomatic and not spontaneously reported by patients. This highlights the importance of actively searching for this sign in the physical exam of encephalopathic patients because it could indicate an underlying toxic or metabolic cause. Asterixis is usually reversible upon treatment of the underlying cause.
Topics: Humans; Myoclonus; Tremor; Dyskinesias; Brain Diseases; Carbamazepine
PubMed: 38541088
DOI: 10.3390/medicina60030362 -
Cureus Jul 2023Toxic epidermal necrolysis (TEN) is a rare fatal mucocutaneous blistering disorder that can have varied underlying triggers. The percentage of body surface area (BSA)...
Toxic epidermal necrolysis (TEN) is a rare fatal mucocutaneous blistering disorder that can have varied underlying triggers. The percentage of body surface area (BSA) that is impacted by erosive blistering is what separates it from Steven Johnson syndrome (SJS), both of which have the same underlying pathogenesis and are thought to exist on a continuum of disease with TEN being the more serious of the two. Medications are the most frequent cause of TEN/SJS and typically cause disease in both adults and children within eight weeks; however, the median exposure window is four days to four weeks. Nonsteroidal anti-inflammatory drugs, allopurinol, anticonvulsants including lamotrigine, phenytoin, levetiracetam and carbamazepine, antimicrobial sulfonamides, and the antiviral nevirapine are examples of medications that frequently cause TEN/SJS. Here, we are reporting a case of phenytoin-induced TEN highlighting the patient's excellent response to immunomodulating treatment despite 100% involvement of the BSA.
PubMed: 37644929
DOI: 10.7759/cureus.42654 -
Cureus Sep 2023The administration of multiple antiepileptic drugs (AEDs) is standard practice for neurological intensive care unit (ICU) patients who cannot obtain seizure control with... (Review)
Review
The administration of multiple antiepileptic drugs (AEDs) is standard practice for neurological intensive care unit (ICU) patients who cannot obtain seizure control with monotherapy. Phenytoin and levetiracetam continue to be highly utilized AEDs for ICU patients due to their efficacy and relatively low cost. However, there is no randomized control trial to date that assesses the efficacy outcomes of the concurrent use of these two medications for ICU patients in convulsive or silent status epilepticus that combats the toxicity with increasing dosages of a single drug by itself. Here, we have analyzed several studies published over the past two decades to better understand whether the concomitant use of these two medications is more efficacious in treating unremitting seizures in ICU patients. Several factors influence which AED is a better fit for ICU patients due to the complexity of their clinical state. Risk for drug interactions, increased incidence of renal and hepatic impairment, and higher need for patient monitoring are daily barriers that determine AED use. After analysis of past research, while the efficacy of concurrent use of levetiracetam and phenytoin is still not fully clear, we offer the "Arrowhead Rationale" for such dual therapy in a subset of patients at our tertiary care trauma and stroke center in Southern California.
PubMed: 37790049
DOI: 10.7759/cureus.44547