Phenobarbital Concentrations Research Articles

Thromboelastography in dogs with idiopathic epilepsy treated with phenobarbital monotherapy

AbstractBackgroundThromboelastography (TEG) is an effective technique to assess the efficiency of coagulation. Phenobarbital (PB) can induce hematological and coagulation disorders in both animals and humans, but its effects on hemostasis have been little investigated and are poorly understood in dogs.ObjectivesThe aim of this article was to assess coagulation using TEG in a population of dogs with idiopathic epilepsy treated with PB.Material and MethodsProspective observational study. TEG was performed in blood samples from dogs with idiopathic epilepsy that were divided in three groups: Two groups of treated dogs that were on phenobarbital treatment for less or more than 6 months, and a control group of healthy dogs. Duration of treatment, dose, phenobarbital serum concentration and selected hematological and biochemical parameters were evaluated and correlated with the TEG results.ResultsNo statistically significant differences were found between groups. None of the animals appeared to be in a hypo‐ or hypercoagulable state, however 9/19 (47,4%) dogs were classified as hyper‐fibrinolytic. A statistically significant negative relationship between MA and G values and increased fibrinolytic activity (LY30) were found. No statistically significant relationship was found between PB dose or PB blood levels and TEG parameters in either group. No bleeding complications were observed.DiscussionThe rise in fibrinolysis might be due to hepatic damage from PB, as indicated by elevated liver enzymes in many dogs with abnormal fibrinolytic patterns. Although TEG showed hyperfibrinolysis in some dogs, the presence of primary or secondary hyperfibrinolysis could not be confirmed due to the lack of D‐dimer measurements and liver biopsy. TEG’s sensitivity compared to other fibrinolysis biomarkers like PAP might also affect results.ConclusionsTThe cause of hyperfibrinolysis in epileptic dogs treated with phenobarbital remains unclear, with potential links to hepatic effects or handling, and further research is needed to assess its clinical significance.

The effect of oral zonisamide treatment on serum phenobarbital concentrations in epileptic dogs.

Zonisamide is used in dogs for the treatment of epileptic seizures. It is predominantly metabolised by CYP450 hepatic enzymes. When used concurrently with phenobarbital (PB), zonisamide clearance is increased and its elimination half-life decreases. However, the effect that zonisamide may have on serum PB concentrations in dogs has not been previously described. Eight dogs diagnosed with idiopathic epilepsy and two dogs with structural epilepsy commenced zonisamide at 8.0 mg/kg/12 h [7.4-10 mg/kg/12 h] following an increase in the frequency of epileptic seizures. Nine dogs were receiving PB every 12 h (4.2 mg/kg/12 h [3.8-6 mg/kg/12 h]), and one dog was receiving PB every 8 h (6 mg/kg/8 h). Following the addition of zonisamide and despite no increase in PB dosage, an increase in phenobarbital serum PB concentration was observed in 9 out of 10 dogs in subsequent measurements. In five dogs, phenobarbital serum concentrations were raised to concentrations higher than the reported hepatotoxic concentrations (trough>35 mg/L). This required a reduction in daily doses of PB. This case series suggests that zonisamide affects the metabolism of PB and causes an increase in PB serum concentrations over time.

Evaluation of Phenobarbital Adsorption Efficiency on Biosorbents or Activated Carbon Obtained from Adansonia Digitata Shells.

The removal of pharmaceutically active compounds present in relatively low concentration in wastewater is critical. This is because they have a severe, negative impact on life and the environment. To address this issue, adsorption was used, which is an effective wastewater treatment method for removing substances found in low concentrations in water. This study compared the adsorption performance of active carbon to three biosorbents derived from Adansonia digitata shells. The adsorbents were prepared and characterized using TGA, SEM, EDX, and FTIR analyses and pHPZC. To better understand the adsorption process, equilibrium and reaction kinetics studies were conducted. The effect of contact time, initial phenobarbital concentration, adsorbent mass, and pH was investigated in static conditions. The adsorption results revealed that the biosorbent B3 has a higher affinity for the eliminated compound, with an equilibrium time of 60 min and an adsorption capacity of 47.08 mg/g at an initial concentration of 50 mg/L. The experimental data are consistent with Langmuir and Sips adsorption isotherm models, and with the pseudo-second order and Elovich models for kinetics description. This indicates strong interactions between the adsorbent materials and the pharmaceutical micropollutant. Based on these findings, it appears that, among the tested materials, B3 biosorbent is the most efficient for removing phenobarbital present in low concentrations in water.

A retrospective evaluation of phenobarbital-induced hematologic changes in 69 cats.

Phenobarbital (PB) is used as a first-line treatment for recurrent epileptic seizures in cats. While hematologic abnormalities are well-known side effects of antiepileptic therapy with PB in humans and dogs, little is known about such alterations in cats. The aim of this retrospective study was to investigate the prevalence and clinical relevance of cytopenia during PB treatment in cats. In this single-center, retrospective clinical study, 69 cats-with suspected idiopathic epilepsy admitted to the Small Animal Clinic of the University of Veterinary Medicine in Vienna (VMU)-were included. A complete blood count for each patient was performed, and changes in hematocrit, leukocytes, neutrophils, and thrombocytes were documented and graded. Fifty-three out of 69 cats (76.8%) showed cytopenias with a reduction of at least one cell fraction during PB treatment. The most frequent change was neutropenia (60%), followed by leukopenia (49.3%), thrombocytopenia (24.1%), and anemia (20.3%). Most of the changes were mild or moderate; only one patient (1.5%) showed severe leukopenia and neutropenia, and one was a life-threatening neutropenia (1.5%) with a serum PB concentration within or even below the therapeutic range. These patients did not present with clinical symptoms other than those related to epileptic episodes. Cats who received combination therapy showed lower hematocrits than those who received monotherapy. A tendency for leukocytes and neutrophils to decrease during PB treatment was also seen. Blood cytopenias may frequently occur in cats on chronic PB therapy, even when serum drug levels are within the therapeutic range. However, clinical signs are typically mild to moderate and rarely severe.

Study of fingolimod, nitric oxide inhibitor, and P-glycoprotein inhibitor in modulating the P-glycoprotein expression via an endothelin-sphingolipid pathway in an animal model of pharmacoresistant epilepsy.

The overexpression of P-glycoprotein (P-gp) contributes to drug resistance in patients with epilepsy, and the change of P-gp expression located at the blood-brain barrier alienates the anti-seizure effects of P-gp substrates. Thus, the present study explored the effect of fingolimod (FTY720) acting through an endothelin-sphingolipid pathway on P-gp-induced pentylenetetrazol (PTZ)-kindled phenobarbital (PB)-resistant rats. PTZ kindling (30 mg/kg; i.p.) and PB (40 mg/kg; orally) were used to develop an animal model of refractory epilepsy. The effect of Fingolimod on seizure score (Racine scale), plasma and brain levels of PB (high-performance liquid chromatography), and blood-brain barrier permeability (Evans blue dye) was determined. Further, Fingolimod's neuroprotective effect was determined by measuring the levels of various inflammatory cytokines, oxidative stress parameters, and neurotrophic factors in rat brain homogenate. The Fingolimod's effect on P-gp expression was estimated by reverse transcriptase-polymerase chain reaction and immunohistochemistry in rat brain. The H and E staining was done to determine the neuronal injury. Fingolimod significantly (P < 0.001) reduced the seizure score in a dose-dependent manner and alleviated the blood-brain barrier permeability. It decreased the P-gp expression, which further increased the brain PB concentration. Fingolimod significantly (P < 0.01) reduced oxidative stress as well as inflammation. Moreover, it attenuated the raised neuronal injury score in a resistant model of epilepsy. The modulation of the P-gp expression by Fingolimod improved drug delivery to the brain in an animal model of refractory epilepsy. Therefore, S1P signaling could serve as an additional therapeutic target to overcome refractoriness.

Does switching brands matter? Complications associated with switching between phenobarbital brands in two dogs with idiopathic epilepsy

AbstractSwitching between brands of the same antiseizure medication has been associated with a loss of epileptic seizure control in people. No such reports are available in the veterinary literature. Here, we describe two cases in which client‐owned dogs with idiopathic epilepsy experienced complications following phenobarbital brand switch, despite no change in the administered dosage. Both dogs had been on treatment with oral phenobarbital for at least 23 months without complications. Following brand switching, one dog became markedly sedated, ataxic and anorexic, and the other dog experienced severe cluster seizures. The measured serum phenobarbital concentrations were significantly altered from the previously measured pre‐brand switching concentrations. Echoing what has been described in human medicine, these cases suggest that therapeutic complications can occur when switching phenobarbital brand in chronically treated dogs with idiopathic epilepsy. Such complications should be considered when modulating antiseizure treatment in dogs. The exact cause for the resulting complications is unclear.

Formulation and stability study of an oral paediatric phenobarbital 1% solution containing hydroxypropyl-β-cyclodextrins

ObjectivesPhenobarbital is a barbiturate, used to treat focal and generalised epilepsy. Since the end of marketing of the oral solution KANEURON in 2017, phenobarbital tablets remain the only available dosage...

Study of phenobarbital removal from the aqueous solutions employing magnetite-functionalized chitosan.

Due to its wide use in anticonvulsant pharmacotherapy, phenobarbital (PHEN) is an aquatic contaminant with a high prevalence in the environment. In this adsorption study, chitosan and chitosan-based magnetic adsorbents containing different amounts of incorporated magnetite (CS, CS·Fe3O4 1:1, CS·Fe3O4 1:5, and CS·Fe3O4 1:10) were used for phenobarbital removal. The magnetic adsorbents were synthesized by co-precipitation method and characterized through FTIR, XRD, MEV, and VSM analysis. In PHEN adsorption, the equilibrium and adsorption kinetic were better adjusted by the Sips and pseudo-second-order model, respectively. Among the four nanoadsorbents used, the maximum phenobarbital adsorption capacity was 94.60mgg-1 using 25mg of CS·Fe3O4 1:5, with a concentration of PHEN (50mg L-1), pH 7.0 at room temperature. The parameters of pH, adsorbent dosage, ionic strength, and thermodynamic study were tested for the adsorbent with the highest performance (CS·Fe3O4 1:5). The nanoadsorbent demonstrates efficiency in the removal of the contaminant for diverse adsorption cycles. Finally, the protocol employing magnetic adsorbents dispenses the subsequent steps of filtration and centrifugation.

Safety and efficacy of cannabidiol-cannabidiolic acid rich hemp extract in the treatment of refractory epileptic seizures in dogs.

The use of cannabidiol (CBD) in childhood refractory seizures has become a common therapeutic approach for specific seizure disorders in human medicine. Similarly, there is an interest in using CBD, cannabidiolic acid (CBDA) or cannabinoid-rich hemp products in the treatment of idiopathic epilepsy in dogs. We aimed to examine a small cohort in a pilot investigation using a CBD and CBDA-rich hemp product for the treatment of refractory epileptic seizures in dogs. Fourteen dogs were examined in a 24-week randomized cross-over study being provided placebo or CBD/CBDA-rich hemp extract treatment at 2 mg/kg orally every 12 h for each 12-week arm of the study. Serum chemistry, complete blood counts, serum anti-seizure medication (ASM) concentrations and epileptic seizure frequency were followed over both arms of the cross-over trial. Results demonstrated that besides a mild increase in alkaline phosphatase, there were no alterations observed on routine bloodwork at 2, 6, and 12 weeks during either arm of the study. Epileptic seizure frequency decreased across the population from a mean of 8.0 ± 4.8 during placebo treatment to 5.0 ± 3.6 with CBD/CBDA-rich hemp extract (P = 0.02). In addition, epileptic seizure event days over the 12 weeks of CBD/CBDA-rich hemp treatment were 4.1 ± 3.4, which was significantly different than during the 12 weeks of placebo treatment (5.8 ± 3.1; P =0.02). The number of dogs with a 50% reduction in epileptic activity while on treatment were 6/14, whereas 0/14 had reductions of 50% or greater while on the placebo (P = 0.02). No differences were observed in serum zonisamide, phenobarbital or bromide concentrations while on the treatment across groups. Adverse events were minimal, but included somnolence (3/14) and transient increases in ataxia (4/14) during CBD/CBDA-rich hemp extract treatment; this was not significantly different from placebo. This further indicates that providing CBD/CBDA-rich hemp extract during refractory epilepsy (only partially responsive to ASM), in conjunction with other ASM appears safe. Based on this information, the use of 2 mg/kg every 12 h of a CBD/CBDA-rich hemp extract can have benefits in reducing the incidence of epileptic seizures, when used concurrently with other ASMs.

Clinical Observations Associated with Phenobarbital Serum Monitoring to Manage Epilepsy in a California Sea Lion with Domoic Acid Toxicosis

The marine algal toxin domoic acid is an important threat to marine mammal health, and exposure can lead to both acute neurologic signs and a chronic epileptic syndrome in California sea lions (Zalophus californianus). Phenobarbital has been used for several decades to manage seizures, although reports are limited correlating dosing, serum monitoring and clinical efficacy in this species. This report details serum monitoring over 33 months in an 8-year-old male sea lion. Seizure control was achieved when phenobarbital concentrations were above 18 μg/mL, and sedation and ataxia were noted when concentrations were above 35 μg/mL. There was no clinically significant difference between phenobarbital concentrations resulting from once-daily versus twice-daily dosing. Serum levels remained detectable as far as 101 days after administration, and remained stable during periods of prolonged anorexia, although dramatic decreases in serum concentrations were noted immediately after normal eating resumed. For this animal, a serum phenobarbital target range of 20–30 μg/mL was achievable with a dose of 1.5 mg/kg once daily followed by therapeutic monitoring, and this is a reasonable recommended concentration and initial dose for clinicians treating this species. Long-term seizure control may be difficult to achieve with anti-epileptic drugs such as phenobarbital alone, and further research is needed to make novel options useful for clinical management of biotoxin-related neurologic disease in this aquatic species.

Treatment of Canine Idiopathic Epilepsy - Clinical Picture after Drug Interaction

Background: The large number of diseases demand perennial development of the pharmaceutical industry. The drug-testing phase is essential to make them available safely. Awareness of pharmacological properties, adverse effects and drug interactions is required. Drug interactions are common in veterinary medicine and should be avoided. At times, epileptic seizures require polydrug therapy, predisposing patients to drug interactions. The interaction between carbamazepine and phenobarbital reported in the literature is an example. The aim of this paper is to report a clinical picture of drug interaction in the treatment of idiopathic epilepsy. Case: A 1-year-old Border Collie male dog, was admitted at the Veterinary Hospital of the Federal University of Lavras in post-ictal. The tutor reported that a year ago the animal had epileptic seizures and clusters with intervals of 21 to 25 days. Despite the continued use of previously prescribed phenobarbital (7.4 mg/kg, v.o., BID, until new recommendations) and carbamazepine (7.5 mg/kg, v.o., BID, until new recommendations), seizure control was not achieved. The physical examination indicated, tachypnea, ptialism, mydriasis, intense fatigue, and alienation from the environment. The patient did not respond to the threat-reflex test. Blood count, hepatic and renal blood chemistry, serum electrolyte (potassium, sodium, calcium and phosphorus), and phenobarbital dosages were requested. Based on the animal's history, breed characteristics, and alterations in the physical examination associated with normal results in complementary exams, idiopathic epilepsy was diagnosed. After analyzing the case, it was observed that the inefficiency in the control of seizures was possibly due to the drug interaction between phenobarbital and carbamazepine. Carbamazepine and phenobarbital reciprocally reduce their half-lives. To confirm the raised hypothesis, the serum concentration of carbamazepine was gradually reduced through weaning from its dose administered to the patient. Serial dosage of the concentration of phenobarbital in the bloodstream was performed. As a result, the serum phenobarbital, previously dosed at a concentration of 13.3 mg/dL with concomitant administration of carbamazepine, increased to 22 mg/dL 40 days after the beginning of weaning from carbamazepine (T0), and then to 36 mg/dL 100 days after T0. There was an increase in the concentration of phenobarbital in the bloodstream while the serum concentration of carbamazepine declined. The patient spaced out his seizures to every 50 to 60 days with phenobarbital monotherapy at a dose of 6 mg/kg. Discussion: Efficient control of clusters, such as the reduction of seizures by 50%, was only possible due to the meticulous perception of the possible interaction reported in medicine. Carbamazepine and phenobarbital are P450 isoenzyme inducers. The concomitant administration of both drugs potentiated the action of isoenzymes in the hepatic microsomal system, which led to an accelerated metabolic processing of the drugs. After weaning from carbamazepine, that is, reducing the action of carbamazepine on the isoenzymes of the P450 enzyme system, the concentration of phenobarbital normalized at 36 mg/dL. Such concentration is within the reference range reported in the literature: 25 mg/dL to 35 mg/dL of serum phenobarbital for treatment efficacy. Therefore, the control of convulsive crises was achieved. The increase in the concentration of phenobarbital due only to weaning from carbamazepine, even after decreasing the daily dose of barbiturate prescribed to the animal, contributed to evidence of the interaction of these drugs. It is noted that prior knowledge of pharmacological properties, careful study of the patient's history, and the cooperation of the tutor were essential for the therapeutic success and practice of evidence-based veterinary medicine. Keywords: drug interaction, carbamazepine, phenobarbital, P450 enzyme. Título: Tratamento da epilepsia idiopática canina - quadro clínico após interação medicamentosa. Descritores: interação medicamentosa, carbamazepina, fenobarbital, enzima P450.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

The effect of nonadherence on phenobarbital concentrations and recommendations on the replacement dose using Monte Carlo simulation.

To determine the impacts of missed phenobarbital (PB) doses on its pharmacokinetics and to investigate the appropriate replacement dosing scheme for various PB missed dose scenarios. Monte Carlo simulations were performed using parameters from the selected population pharmacokinetic study. The impacts of missed PB dose and the proper replacement dosing scheme were assessed based on the percent deviation of simulated concentrations outside the reference range from the full adherence scenario. The impact of missed PB dose on its concentrations depended on the daily dose. The replacement with a respective regular dose and one and a half regular dose was appropriate for the one and two missed doses scenarios for patients receiving PB monotherapy. For patients receiving PB with valproic acid or phenytoin, the same replacement scheme was still appropriate. The results also indicated that weight did not influence the proper replacement dosing scheme. The impacts of missed PB doses on its pharmacokinetics were identified and the proper replacement dosing schemes for different missed dose scenarios were proposed. These schemes should be implemented based on the clinician's justification of the patient's seizure control.

Development a coordination polymer based nanosensor for phenobarbital determination in exhaled breath condensate

In this study, a fluorometric probe based on luminol-terbium coordination polymer nanoparticles (luminol-Tb CP NPs) is validated for the quantification of phenobarbital in the exhaled breath condensate collected from expiratory circuit of the mechanical ventilator (MVEBC). It relies on the coordination of phenobarbital to luminol-Tb CP NPs which casing an aggregation-induced fluorescence enhancement of probe owing to the increasing the system rigidity and the decreasing the nonradiative decay rate. As the increase in response intensity is proportional to phenobarbital amount, a method is offered for its determination in MVEBC. This method presents a linear relationship with phenobarbital concentration in the range of 0.1–10.0 mg.L−1 with a limit of detection of 0.024 mg.L−1 and the relative standard deviation of 3.6%. The proposed method is used in MVEBC of the pre-term newborn babies receiving phenobarbital under mechanical ventilator.

Telmisartan as an add-on treatment for dogs with refractory idiopathic epilepsy: a nonrandomized, uncontrolled, open-label clinical trial.

To evaluate the effect on seizure frequency of add-on telmisartan treatment in dogs with refractory idiopathic epilepsy. 11 client-owned dogs with idiopathic epilepsy and ≥ 2 generalized seizures/mon that were currently being treated with ≥ 2 antiepileptic drugs. Telmisartan was administered at a dosage of 0.25 to 1 mg/kg, PO, every 12 hours for 4 to 16 months. Seizure frequencies before and during telmisartan treatment were recorded. 10 dogs completed the 4-month treatment protocol. One dog was excluded owing to a transient increase in serum creatinine concentration; no adverse effects of telmisartan were observed in the remaining 10 dogs. A reduction in seizure frequency greater than an estimated expected placebo effect of 30% was evident in 7 of the 10 dogs. Long-term (12 to 16 months) follow-up information was available for 6 dogs, of which 4 had a further reduction in seizure frequency. Differences in seizure frequency were not statistically significant. No significant difference was found in serum phenobarbital concentration throughout the treatment period in the 7 dogs that were tested. Telmisartan has the potential to reduce seizure frequency when administered as an add-on antiepileptic drug in dogs with refractory idiopathic epilepsy. A randomized, double-blind, placebo-controlled trial is needed to determine the true efficacy of telmisartan. On the basis of our results, a sample size of 54 dogs with refractory idiopathic epilepsy would be needed.

Influence of Umbelliferone on the Anticonvulsant and Neuroprotective Activity of Selected Antiepileptic Drugs: An In Vivo and In Vitro Study.

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.

Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

Serum NMR metabolomics uncovers multiple metabolic changes in phenobarbital-treated dogs

IntroductionPhenobarbital is a commonly used anticonvulsant for the treatment of canine epileptic seizures. In addition to its central nervous system (CNS) depressing effects, long-term phenobarbital administration affects liver function. However, broader metabolic consequences of phenobarbital treatment are poorly characterized.ObjectivesTo identify metabolic changes in the sera of phenobarbital-treated dogs and to investigate the relationship between serum phenobarbital concentration and metabolite levels.MethodsLeftovers of clinical samples were used: 58 cases with phenobarbital concentrations ranging from 7.8 µg/mL to 50.8 µg/mL, and 25 controls. The study design was cross-sectional. The samples were analyzed by a canine-specific 1H NMR metabolomics platform. Differences between the case and control groups were evaluated by logistic regression. The linear relationship between metabolite and phenobarbital concentrations was evaluated using linear regression.ResultsIncreasing concentrations of glycoprotein acetyls, LDL particle size, palmitic acid, and saturated fatty acids, and decreasing concentrations of albumin, glutamine, histidine, LDL particle concentration, multiple HDL measures, and polyunsaturated fatty acids increased the odds of the sample belonging to the phenobarbital-treated group, having a p-value < .0033, and area under the curve (AUC) > .7. Albumin and glycoprotein acetyls had the best discriminative ability between the groups (AUC: .94). No linear associations between phenobarbital and metabolite concentrations were observed.ConclusionThe identified metabolites are known to associate with, for example, liver and CNS function, inflammatory processes and drug binding. The lack of a linear association to phenobarbital concentration suggests that other factors than the blood phenobarbital concentration contribute to the magnitude of metabolic changes.

Factors affecting serum phenobarbital concentration changes in pediatric patients receiving elixir and powder formulations

BackgroundPhenobarbital (PB) is commonly used as elixir and powder formulations in pediatric care. Its dose adjustment is performed based on individual drug concentration monitoring. Few studies have comprehensively analyzed the variation factors for serum PB concentration. In this study, we retrospectively investigated the factors that influence serum PB concentration and assessed the impacts of dosage formulation and administration route.MethodsThis retrospective cohort study covered clinical data from January 2007 to September 2019 at Mie University Hospital. The present study included 60 pediatric patients administered the elixir and powder of PB through oral route and enteral tube. Simple and multiple linear regression analyses were performed to identify the risk factors that affect the weight-corrected PB serum concentration/dose (C/D) ratio in pediatric patients. Six subgroups were also established according to the concomitant use of drugs that potentially inhibit PB metabolism, dosage formulation, and administration route to investigate the difference in the PB C/D ratio among the subgroups.ResultsA significant regression equation to predict the PB C/D ratio was found through simple and multiple linear regression analyses, with an adjusted coefficient of determination of 0.53 (p < 0.001). Further, the concomitant uses of valproic acid (VPA) or amiodarone, which were the only two drugs seen in this study as potential inhibitors of PB, was found to have the greatest effect on the PB C/D ratio (standardized partial regression coefficient (β) = 0.543, p < 0.001). Furthermore, a significant difference in the PB C/D ratio was found between the subgroups classified by the concomitant use of VPA or amiodarone (p = 0.002). However, there were no significant correlations between the PB C/D ratio, dosage formulation, and administration route.ConclusionsThe most influential factor on the PB C/D ratio was the concomitant use of VPA or amiodarone with PB. This result could provide an important perspective in pediatric drug therapy where elixir and powder formulations are administered via the oral route and enteral tube.

Anticonvulsant Effectiveness and Neurotoxicity Profile of 4-butyl-5-[(4-chloro-2-methylphenoxy)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) in Mice

Protective (antiseizure) effects of 4-butyl-5-[(4-chloro-2-methylphenoxy)-methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (TPL-16) and acute neurotoxic effects were determined in the tonic-clonic seizure model and rotarod test in mice. The interaction profile of four classic antiepileptic drugs (carbamazepine, phenobarbital, phenytoin and valproate) with TPL-16 was also determined in the tonic-clonic seizure model in mice. The protective effects of TPL-16 from tonic-clonic seizures (as ED50 values) and acute neurotoxic effects of TPL-16 (as TD50 values) were determined in 4 pretreatment times (15, 30, 60 and 120 min after its i.p. administration), in adult male albino Swiss mice. The interaction profile of TPL-16 with carbamazepine, phenobarbital, phenytoin and valproate in the tonic-clonic seizure model was determined with isobolographic analysis. Total concentrations of carbamazepine, phenobarbital, phenytoin and valproate were measured in the mouse brain homogenates. The candidate for novel antiepileptic drug (TPL-16) administered separately 15 min before experiments, has a beneficial profile with protective index (as ratio of TD50 and ED50 values) amounting to 5.58. The combination of TPL-16 with valproate produced synergistic interaction in the tonic-clonic seizure model in mice. The combinations of TPL-16 with carbamazepine, phenobarbital and phenytoin produced additive interaction in terms of protection from tonic-clonic seizures in mice. None of the total brain concentrations of classic AEDs were changed significantly after TPL-16 administration in mice. Synergistic interaction for TPL-16 with valproate and the additive interaction for TPL-16 with carbamazepine, phenobarbital and phenytoin in the tonic-clonic seizures in mice allows for recommending TPL-16 as the promising drug for further experimental and clinical testing.