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Pharmaceutics Jan 2024Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to...
Hot melt extrusion (HME) offers a high-throughput process to manufacture amorphous solid dispersions. A variety of experimental and model-based approaches exist to predict API solubility in polymer melts, but these methods are typically aimed at determining the thermodynamic solubility and do not take into account kinetics of dissolution or the associated degradation of the API during thermal processing, both of which are critical considerations in generating a successful amorphous solid dispersion by HME. This work aims to develop a material-sparing approach for screening manufacturability of a given pharmaceutical API by HME using physically relevant time, temperature, and shear. Piroxicam, ritonavir, and phenytoin were used as model APIs with PVP VA64 as the dispersion polymer. We present a screening flowchart, aided by a simple custom device, that allows rapid formulation screening to predict both achievable API loadings and expected degradation from an HME process. This method has good correlation to processing with a micro compounder, a common HME screening industry standard, but only requires 200 mg of API or less.
PubMed: 38258087
DOI: 10.3390/pharmaceutics16010076 -
Frontiers in Neurology 2023Post-traumatic seizure (PTS) is a well-known complication of traumatic brain injury (TBI). The objective of this study was to identify risk factors associated with...
OBJECTIVE
Post-traumatic seizure (PTS) is a well-known complication of traumatic brain injury (TBI). The objective of this study was to identify risk factors associated with breakthrough early PTS in TBI patients receiving phenytoin prophylaxis.
METHODS
This was a single-centered retrospective study including adult patients admitted to the intensive care unit (ICU), had a TBI, and started on phenytoin for seizure prophylaxis within 24 h of admission. The primary outcome was the incidence and factors associated with early PTS, defined as a confirmed seizure on a continuous electroencephalogram within 7 days of TBI. Secondary outcomes included the association between early post-traumatic seizures and ICU length of stay, hospital length of stay, and in-hospital mortality.
RESULTS
A total of 105 patients were included in the final analysis. Patients with early PTS were older (65 vs. 48 years old, = 0.01), had a higher Marshall score (5 vs. 2, = 0.01), were more likely to have a Marshall score > 2 (73 vs. 37%, = 0.01), and had more neurosurgeries for hematoma evacuation (57 vs. 19%, = 0.01). In patients with early PTS, 57% had a level at the time of seizure, and of those, 87.5% had a therapeutic level (>10 mcg/mL). Patients with early PTS had a longer ICU length of stay (14.7 vs. 5.9 days, = 0.04) and a greater proportion of hospital mortality (21 vs. 2%, = 0.02).
CONCLUSION
Patients with higher age, Marshall score, and neurosurgical procedures for hematoma evacuation had higher incidences of breakthrough early PTS despite the use of phenytoin prophylaxis. The majority of patients with early PTS had therapeutic phenytoin levels at the time of seizure when a level was available; however, approximately half (43%) did not have a level.
PubMed: 38239322
DOI: 10.3389/fneur.2023.1329042 -
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 -
The Journal of Toxicological Sciences 2024Cleft palate (CP) is one of the most common birth defects and is caused by a combination of genetic and/or environmental factors. Environmental factors such as...
Cleft palate (CP) is one of the most common birth defects and is caused by a combination of genetic and/or environmental factors. Environmental factors such as pharmaceutical exposure in pregnant women are known to induce CP. Recently, microRNA (miRNA) was found to be affected by environmental factors. The aim of the present study was to investigate the involvement of miRNA against phenytoin (PHE)-induced inhibition of proliferation in human embryonic palatal mesenchymal (HEPM) cells. We demonstrated that PHE inhibited HEPM cell proliferation in a dose-dependent manner. We found that treatment with PHE downregulated cyclin-D1 and cyclin-E expressions in HEPM cells. Furthermore, PHE increased miR-4680-3p expression and decreased two downstream genes (ERBB2 and JADE1). Importantly, an miR-4680-3p-specific inhibitor restored HEPM cell proliferation and altered expression of ERBB2 and JADE1 in cells treated with PHE. These results suggest that PHE suppresses cell proliferation via modulation of miR-4680-3p expression.
Topics: Pregnancy; Humans; Female; Phenytoin; MicroRNAs; Cell Proliferation; Palate
PubMed: 38191190
DOI: 10.2131/jts.49.1 -
Clinical Case Reports Jan 2024Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome with central nervous system (CNS) symptoms usually related to autoregulatory cerebral failure...
Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome with central nervous system (CNS) symptoms usually related to autoregulatory cerebral failure and high blood pressure. Neuroimaging is critical to diagnosis. Neurological presentations of COVID-19 disease are categorized into CNS symptoms and peripheral nervous system (PNS) symptoms. The patient was a 15-year-old female with SARS-CoV-2 pneumonia who developed PRES with a typical clinical and radiological appearance. She was treated with dexamethasone, phenytoin, sodium valproate and remdesivir. The patient was discharged after recovery of symptoms and was in good general condition. It is recommended that in patients affected by COVID-19 with neurological symptoms, the PRES can be considered in the differential diagnosis.
PubMed: 38188851
DOI: 10.1002/ccr3.8336 -
Heliyon Jan 2024This study investigates the novel application of Phenyl Boronic Acid Functionalized-Quercetin nanoparticles (PBA-Qt NPs) in the context of antibacterial and diabetic...
This study investigates the novel application of Phenyl Boronic Acid Functionalized-Quercetin nanoparticles (PBA-Qt NPs) in the context of antibacterial and diabetic wound healing. The research reveals a multifaceted approach, encompassing physicochemical characterization, antioxidant activity, antibacterial potential, and wound healing efficacy. The purpose of the study was to improve wound healing and antibacterial effects of quercetin and its esterified nanoparticles with phenyl boronic acid (PBA-Qt) compared with phenytoin streptozotocin-induced diabetic rats as a model. PBA-Qt NPs were confirmed using TLC, SEM, and FTIR. They exhibited superior DPPH scavenging (84.2 ± 0.12 %) compared to PBA (59.00 ± 0.18 %) and quercetin (79.02 ± 0.17 %). PBA-Qt showed significant antimicrobial properties with ZOI against Gram-negative (30.34 ± 0.02) and Gram-positive bacteria (25.40 ± 0.03). The MIC for was 1.41 ± 0.03 μg/100 μL, and for , it was 8.25 ± 0.02 μg/100 μL. The MBC against was 4.33 ± 0.02 μg/100 μL, and for , it was 8.25 ± 0.02 μg/100 μL. PBA-Qt NPs reduced MIC for both Gram-positive and Gram-negative bacteria compared to quercetin. They enhanced wound healing by 60-99 % in infected diabetic rats, outperforming phenytoin. PBA-Qt NPs stimulated angiogenesis, tissue repair, and regeneration, improving wound closure. In diabetic and non-diabetic wounds, PBA-Qt NPs demonstrated superior wound contraction and granulation tissue formation. In conclusion, PBA-Qt nanoparticles are promising for treating diabetic chronic wounds due to reduced irritation and enhanced antibacterial and wound-healing properties.
PubMed: 38169972
DOI: 10.1016/j.heliyon.2023.e23452 -
Cureus Dec 2023Sepsis is a life-threatening emergency that arises owing to a dysregulated host response to infection, leading to existence organ dysfunction. Vitamin C administration...
Sepsis is a life-threatening emergency that arises owing to a dysregulated host response to infection, leading to existence organ dysfunction. Vitamin C administration has led to a lower mortality rate in sepsis. N-acetylcysteine (NAC) treatment during sepsis improves hepatic function and enhances tissue oxygenation. The objective of this case report is to investigate the synergistic effect of the combination of vitamin C, thiamine, and NAC in delaying sepsis cascade and prolongation of survival time. In this case report, an oral dose of vitamin C 500 mg three times daily in combination with IV thiamine 100 mg three times daily, IV NAC, and hydrocortisone stress dose resulted in 12 days of survival of an immunocompromised patient with ventilator-associated pneumonia on single anti-pseudomonas beta-lactam antibiotic. The patient was a 60-year-old Malay female with previous bone marrow transplantation surgery and a medical history of ischemic stroke on phenytoin and valproate therapy. The patient was transferred to a medical ward in Penang General Hospital, Malaysia, due to community-acquired pneumonia. She was on ceftriaxone for five days, then sedated and ventilated in the ICU, with a shift to cefepime for three days, which was then changed to meropenem for nine days until the last day of life. Total anti-pseudomonas coverage was 12 days. The patient had multiple comorbidities from phenytoin-induced hepatic encephalopathy, acute kidney injury, and three sessions of hemodialysis. IV vitamin C was not available, so an oral dose was administered with potential efficacy in delaying the sepsis inflammatory cascade, leading to the use of a single (not double) anti-pseudomonas antibiotic for 12 days. Prolonged survival duration may be expected in the case of normal bone marrow patients with ventilator-associated pneumonia sepsis. In conclusion, Vitamin C, thiamine, and NAC combination resulted in delayed sepsis progression for 12 days and the survival of the immunocompromised patient on a single anti-pseudomonas beta-lactam antibiotic.
PubMed: 38169912
DOI: 10.7759/cureus.49868 -
Cureus Nov 2023Epilepsy is not a common cause of morbidity in pregnancy. It has widespread effects on maternal and fetal health necessitating adequate control of seizures. Many...
Epilepsy is not a common cause of morbidity in pregnancy. It has widespread effects on maternal and fetal health necessitating adequate control of seizures. Many anti-seizure medications (ASM) have teratogenic effects on the fetus. We report a case of severe fetal hydantoin syndrome resulting in life-threatening major congenital anomalies. The mother was on phenytoin for the last three years and the pregnancy was not registered. We discuss various features of fetal hydantoin syndrome and the ideal management of epilepsy in pregnancy in brief.
PubMed: 38161950
DOI: 10.7759/cureus.49663 -
Cureus Nov 2023Meningitis caused by bacteria, which is an inflammation of the meninges affecting the pia, arachnoid, and subarachnoid space, is still one of the leading causes of death...
Meningitis caused by bacteria, which is an inflammation of the meninges affecting the pia, arachnoid, and subarachnoid space, is still one of the leading causes of death and morbidity in infants and young children. , group B streptococcus (GBS), type B (Hib), , and have been found to be the most frequent causative agents. Infants and children can have modest, fluctuating, non-specific, or even absent clinical signs of bacterial meningitis. They may include bulging fontanelles, vomiting, diarrhea, respiratory distress, hypothermia, lethargy, irritability, poor feeding, and fever in babies. In this case report, an 18-month-old child presented to a local hospital with complaints of multiple episodes of high-grade fever. After 10 days, his symptoms worsened and he experienced two episodes of seizures at one-day intervals at night. He was taken to Acharya Vinoba Bhave Rural Hospital for further management. Blood investigations revealed seropositive results for dengue virus infection. On MRI and CT scan, it was diagnosed as an old case of subdural hematoma in the right frontotemporal region of the brain. The patient was on intravenous ceftriaxone and phenytoin. Gross motor developmental milestones in children with meningitis can be improved with early integrative neurophysiotherapy and a goal-oriented therapeutic regimen that includes mobility exercises, proprioceptive neuromuscular facilitation techniques, positioning, oromotor retraining, neurodevelopmental techniques, and balance and coordination retraining. A complex case presents with bacterial meningitis, hydrocephalus, and seizure disorder. The bacterial infection inflames the protective membranes of the brain, causing hydrocephalus. Increased cerebrospinal fluid puts pressure on the brain, leading to seizures. Managing these interconnected conditions requires a multidisciplinary approach making it unique, involving infectious disease, neurology, and neurosurgery expertise.
PubMed: 38156138
DOI: 10.7759/cureus.49540 -
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