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Pharmaceutics Oct 2023Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related...
Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy.
Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.
PubMed: 37896215
DOI: 10.3390/pharmaceutics15102455 -
Frontiers in Neurology 2024Poststroke seizure is a potential complication of stroke, which is the most frequent acute symptomatic seizure in adults. Patients with stroke may present with an... (Review)
Review
Poststroke seizure is a potential complication of stroke, which is the most frequent acute symptomatic seizure in adults. Patients with stroke may present with an abnormal or aggressive behavior accompanied by altered mental status and symptoms, such as hemiparesis, dysarthria, and sensory deficits. Although stroke manifestations that mimic seizures are rare, diagnosing poststroke seizures can be challenging when accompanied with negative postictal symptoms. Differential diagnoses of poststroke seizures include movement disorders, syncope, and functional (nonepileptic) seizures, which may present with symptoms similar to seizures. Furthermore, it is important to determine whether poststroke seizures occur early or late. Seizures occurring within and after 7 d of stroke onset were classified as early and late seizures, respectively. Early seizures have the same clinical course as acute symptomatic seizures; they rarely recur or require long-term antiseizure medication. Conversely, late seizures are associated with a risk of recurrence similar to that of unprovoked seizures in a patient with a focal lesion, thereby requiring long-term administration of antiseizure medication. After diagnosis, concerns regarding treatment strategies, treatment duration, and administration of primary and secondary prophylaxis often arise. Antiseizure medication decisions for the initiation of short-term primary and long-term secondary seizure prophylaxis should be considered for patients with stroke. Antiseizure drugs such as lamotrigine, carbamazepine, lacosamide, levetiracetam, phenytoin, and valproate may be administered. Poststroke seizures should be diagnosed systematically through history with differential diagnosis; in addition, classifying them as early or late seizures can help to determine treatment strategies.
PubMed: 38660095
DOI: 10.3389/fneur.2024.1337960 -
BioRxiv : the Preprint Server For... Oct 2023The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric...
OBJECTIVE
The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two sites from the global ENIGMA-Epilepsy working group.
METHODS
A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness.
RESULTS
Across all epilepsies, reduced total cerebellar volume was observed (=0.42). Maximum volume loss was observed in the corpus medullare (=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (= 0.47), Crus I/II (= 0.39), VIIIA (=0.45) and VIIIB (=0.40). Earlier age at seizure onset (=0.05) and longer epilepsy duration (=0.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls.
SIGNIFICANCE
We provide robust evidence of deep cerebellar and posterior lobe subregional grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellum subregions into neurobiological models of epilepsy.
PubMed: 37961570
DOI: 10.1101/2023.10.21.562994 -
Biomedicines Oct 2023Four 5,5'-diphenylhydantoin Schiff bases possessing different aromatic species (-) were recently synthesized and characterized using spectroscopic and electrochemical...
Four 5,5'-diphenylhydantoin Schiff bases possessing different aromatic species (-) were recently synthesized and characterized using spectroscopic and electrochemical tools. The present study aimed to ascertain the anticonvulsant activity of the novel phenytoin derivatives , , , and , containing different electron-donor and electron-acceptor groups, and their possible mechanism of action. The exhibited the highest potency to suppress the seizure spread with ED = 8.29 mg/kg, comparable to phenytoin (ED = 5.96 mg/kg). While did not produce neurotoxicity and sedation, it decreased locomotion and stereotypy compared to control. When administered in combination, the four Schiff bases decreased the phenytoin ED by more than 2× and raised the protective index by more than 7× (phenytoin+). The strongest correlation between in-vivo and docking study results was found for ligands' interaction energies with kappa and delta receptors. These data, combined with the worst interaction energies of our ligands with the mu receptor, suggest that the primary mechanism of their action involves the kappa and delta receptors, where the selectivity to the kappa receptor leads to higher biological effects. Our findings suggest that the four Schiff bases might be promising candidates with potential applications as a safe and effective adjuvant in epilepsy.
PubMed: 38001914
DOI: 10.3390/biomedicines11112912 -
Cureus Jul 2023Stevens-Johnson syndrome (SJS) is a dreaded hypersensitivity reaction and a rare immune disorder. We present a Stevens-Johnson syndrome induced by herbal kadha, which...
Stevens-Johnson syndrome (SJS) is a dreaded hypersensitivity reaction and a rare immune disorder. We present a Stevens-Johnson syndrome induced by herbal kadha, which may be the first case. A ten-year-old boy presented with massive sloughing, redness, oedematous skin, an oral ulcer, and an inability to feed or drink for two days. The present symptoms started after 12 hours of consuming herbal Kadha, given by a private practitioner in clinics where he was treated for fever. After not responding to earlier treatment, the patient was referred to the present Institute. The patient had a history of seizure disorder and had been on tablet phenytoin for seven months with no history of adverse reactions to it. He was treated in the intensive care unit. Fortunately, he responded to treatment and recovered fully. He received treatment in the form of immunoglobulin and steroids. Phenytoin and herbal kadha were withdrawn, and Clobazam was continued. Natural herbal medicines can develop severe adverse effects. Physicians should remain aware that drug interactions can likely be seen with drugs with a narrow therapeutic index combined with herbal preparations. Clinicians should do more research on the interaction between herbal and prescription medications.
PubMed: 37637620
DOI: 10.7759/cureus.42407 -
CNS Drugs Nov 2023Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The...
Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.
BACKGROUND AND OBJECTIVES
Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials.
METHODS
The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly.
RESULTS
This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021.
CONCLUSION
Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.
Topics: Humans; Child; Adult; Female; Middle Aged; Aged; Aged, 80 and over; Male; Anticonvulsants; Phenytoin; Midazolam; Levetiracetam; Valproic Acid; Propofol; Lacosamide; Hospitals, University; Status Epilepticus; Phenobarbital; Benzodiazepines; Medical Records
PubMed: 37979095
DOI: 10.1007/s40263-023-01049-w -
Problemy Endokrinologii Feb 2024Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence... (Review)
Review
RELEVANCE
Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence of NET especially insulinoma.
AIM
Summarizing and analyzing current data on various approaches to the treatment of insulinoma. Our review includes a comprehensive assessment of the advantages and disadvantages of currently available insulinoma treatment methods in comparison with past experience, as well as a review of promising methods that are not currently widely used.
MATERIALS AND METHODS
Analysis of literature from such databases as scientific electronic library elibrary.ru, Pubmed, Google Scholar, MedLine, Scopus and Web of Science.
RESULTS
The most common treatment for insulinoma is surgery. For patients with high operative risk, alternative methods such as alcohol ablation, radiofrequency ablation, and tumor embolization may be used. Medications include the use of somatostatin analogues, diazoxide. The literature describes the potential benefit of the use of beta-blockers, phenytoin, glucagon, however, in clinical trials, these drugs have not demonstrated a significant effect. For the treatment of malignant and metastatically advanced insulinoma, targeted therapy (primarily Everolimus), chemotherapy, as well as embolization (including chemoembolization, radioembolization), radiofrequency ablation (RFA), microwave ablation and cryoablation, ultrasound ablation (HIFU), laser ablation, brachytherapy, irreversible electroporation are used.
CONCLUSION
The study of new drugs is an important task for scientists, among medications the most promising are new generations of somatostatin analogues, targeted drugs and chemotherapy drugs. The rare frequency of insulinoma makes it difficult to conduct randomized controlled trials and prospective studies. That is why physicians and scientists need to maintain close contacts with each other and take into account the experience of treating each patient with such disease, which will help develop effective treatment algorithms in the future.
Topics: Humans; Insulinoma; Prospective Studies; Neuroendocrine Tumors; Apudoma; Pancreatic Neoplasms; Somatostatin
PubMed: 38433541
DOI: 10.14341/probl13281 -
Metabolites Jul 2023The thyroid hormones (THs) regulate various physiological mechanisms in mammals, such as cellular metabolism, cell structure, and membrane transport. The therapeutic...
The thyroid hormones (THs) regulate various physiological mechanisms in mammals, such as cellular metabolism, cell structure, and membrane transport. The therapeutic drugs propylthiouracil (PTU) and phenytoin are known to induce hypothyroidism and decrease blood thyroid hormone levels. To analyze the impact of these two drugs on systemic metabolism, we focused on metabolic changes after treatment. Therefore, in a rat model, the metabolome of thyroid and liver tissue as well as from the blood plasma, after 2-week and 4-week administration of the drugs and after a following 2-week recovery phase, was investigated using targeted LC-MS/MS and GC-MS. Both drugs were tested at a low dose and a high dose. We observed decreases in THs plasma levels, and higher doses of the drugs were associated with a high decrease in TH levels. PTU administration had a more pronounced effect on TH levels than phenytoin. Both drugs had little or no influence on the metabolomes at low doses. Only PTU exhibited apparent metabolome alterations at high doses, especially concerning lipids. In plasma, acylcarnitines and triglycerides were detected at decreased levels than in the controls after 2- and 4-week exposure to the drug, while sphingomyelins and phosphatidylcholines were observed at increased levels. Interestingly, in the thyroid tissue, triglycerides were observed at increased concentrations in the 2-week exposure group to PTU, which was not observed in the 4-week exposure group and in the 4-week exposure group followed by the 2-week recovery group, suggesting an adaptation by the thyroid tissue. In the liver, no metabolites were found to have significantly changed. After the recovery phase, the thyroid, liver, and plasma metabolomic profiles showed little or no differences from the controls. In conclusion, although there were significant changes observed in several plasma metabolites in PTU/Phenytoin exposure groups, this study found that only PTU exposure led to adaptation-dependent changes in thyroid metabolites but did not affect hepatic metabolites.
PubMed: 37512556
DOI: 10.3390/metabo13070847 -
Frontiers in Pharmacology 2023Captisol-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. We aim to compare the intravenous and...
Comparison of pharmacokinetics and safety between CE-fosphenytoin sodium, fosphenytoin sodium, and phenytoin sodium after intravenous and intramuscular administration in healthy volunteers.
Captisol-enabled-fosphenytoin sodium (CE-fosphenytoin sodium) injection is a modified formulation of fosphenytoin sodium. We aim to compare the intravenous and intramuscular bioavailability and safety between CE-fosphenytoin sodium, fosphenytoin sodium (Cerebyx), and phenytoin sodium (intravenous injection only). In pivotal study 1, 54 subjects were divided into three sequence groups that receive intravenous injection of 250 mg of phenytoin sodium equivalent (PE), CE-fosphenytoin sodium (T), or fosphenytoin sodium (R1) and 250 mg of phenytoin sodium (R2) in period 1. After a 14-day washout period, 36 subjects were randomized to two treatment sequence groups (T-R1 or R1-T, = 18 per group) in period 2, in which the subjects who received R2 in period 1 were removed, those who received T in period 1 used R1 (T-R1), while those who previously received R1 used T (R1-T). In pivotal study 2, a single intramuscular dose of T (400 mg PE) or R1 (400 mg PE) was administered according to the individual sequential treatment assignment in each period. There was a washout (14 days) period before receiving the next period study drug. T and R1 have similar pharmacokinetic characteristics regarding total and free phenytoin, showing bioequivalence of both drugs in the intravenous and intramuscular administration. The geometric mean ratio was close to 1 (0.98-1.06). The AUC of total and free phenytoin in subjects who intravenously received T and R1 was very similar to those who received R2, although their C was lower than that of the subjects who received R2. Overall, treatment with T and R1 was safe and well-tolerated, without serious adverse events (SAEs) or grade III adverse events (AEs). With intravenous (i.v.) or intramuscular (i.m.) treatment, the incidence of drug-related AEs using T was similar to that using R1. Treatment with T and R1 had clearly superior tolerability than that with R2. CE-fosphenytoin sodium is a promising substitute for fosphenytoin sodium. http://www.chinadrugtrials.org.cn/, CTR20202154 (11 November 2020).
PubMed: 38044946
DOI: 10.3389/fphar.2023.1204075 -
International Journal of Molecular... Dec 2023Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications... (Review)
Review
Experimental studies reveal that caffeine (trimethylxanthine) at subconvulsive doses, distinctly reduced the anticonvulsant activity of numerous antiseizure medications (ASMs) in rodents, oxcarbazepine, tiagabine and lamotrigine being the exceptions. Clinical data based on low numbers of patients support the experimental results by showing that caffeine (ingested in high quantities) may sharply increase seizure frequency, considerably reducing the quality of patients' lives. In contrast, this obviously negative activity of caffeine was not found in clinical studies involving much higher numbers of patients. ASMs vulnerable to caffeine in experimental models of seizures encompass carbamazepine, phenobarbital, phenytoin, valproate, gabapentin, levetiracetam, pregabalin and topiramate. An inhibition of R-calcium channels by lamotrigine and oxcarbazepine may account for their resistance to the trimethylxanthine. This assumption, however, is complicated by the fact that topiramate also seems to be a blocker of R-calcium channels. A question arises why large clinical studies failed to confirm the results of experimental and case-report studies. A possibility exists that the proportion of patients taking ASMs resistant to caffeine may be significant and such patients may be sufficiently protected against the negative activity of caffeine.
Topics: Humans; Lamotrigine; Oxcarbazepine; Caffeine; Topiramate; Anticonvulsants; Seizures; Calcium Channels
PubMed: 38139396
DOI: 10.3390/ijms242417569