Phenobarbital was synthesized by the German organic chemist Emil Fischer in 1911. It is approved and marketed in the Czech Republic as an antiepileptic in tablet and injection form. Although phenobarbital as a hypnosedative has been outdated for decades, it is still available as a substance and used for the individual compounding of various obsolete mixtures. It is likely that prescribers are unaware of the risks associated with their use. The article presents a brief pharmacological profile of phenobarbital, lists the most often used mixtures, substance consumption and risks associated with its use.
Novorodenecké kŕčové stavy patria medzi urgentné situácie, ktoré si vyžadujú promptnú diagnostiku a adekvátny terapeutický zásah. Zásadným patogenetickým faktorom konvulzií je hyperexcitabilita neurónov, podmienená neukončenou maturáciou nezrelého mozgu. Etiológia kŕčov, gestačný vek a charakter EEG nálezu sú hlavnými prediktormi závažnosti postihnutia. Pre prognózu pacienta je však nemenej dôležitá aj vhodne zvolená liečebná stratégia. Nediagnostikované, nesprávne liečené alebo refraktérne konvulzie vedú k ireverzibilným neurologickým zmenám, majú negatívny dopad na ďalší psychomotorický vývin a sú zaťažené vysokou mierou mortality. V liečbe neonatálnych konvulzií sa okrem všeobecne používaného fenobarbitalu dostávajú do popredia aj ďalšie preparáty s porovnateľnou účinnosťou, ale s nižším výskytom nežiadúcich účinkov. Medzi tieto antikonvulzíva patrí aj levetiracetam, ktorého klinické používanie za nedávne obdobie výrazne vzrástlo a predstavuje akceptovateľnú alternatívu.
Neonatal seizures are one of the most common neurological emergency. Prompt diagnosis and appropriate treatment are crucial for proper patient's management. The neuronal hyperexcitability of developing brain is an essential predisposing factor for convulsions. Brain damage is determined by seizures etiology, gestational age and EEG findings. However, an adequate therapeutic strategy is no less important for the patient's prognosis. Undiagnosed, improperly treated or refractory convulsions lead to irreversible neurological changes. Seizures can have a negative impact on further neuropsychological development and are associated with a high mortality rate. Phenobarbital is still the first line treatment for neonatal seizures, anyway, new anticonvulsive drugs are entering clinical practice. They have comparable effectiveness but lower incidence of adverse effects. One of acceptable drug from this category is Levetiracetam, which recently has significantly increased in therapeutic use.
- MeSH
- antikonvulziva terapeutické užití MeSH
- fenobarbital škodlivé účinky terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- křeče u dětí * farmakoterapie MeSH
- levetiracetam * aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- mozek růst a vývoj MeSH
- novorozenec MeSH
- záchvaty farmakoterapie MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
BACKGROUND: The current study uses a population modeling approach to evaluate and quantify the impact of severity of asphyxia and hypoxic-ischemic encephalopathy (HIE) on the pharmacokinetics of phenobarbital in asphyxiated newborns treated with therapeutic hypothermia. METHODS: Included newborns received phenobarbital (the TOBY trial protocol). 120 plasma samples were available from 50 newborns, median (IQR) weight 3.3 (2.8-3.5) kg and gestational age 39 (39-40) weeks. NONMEM® version 7.2 was used for the data analysis. Age, body weight, sex, concomitant medications, kidney and liver function markers, as well as severity parameters of asphyxia and HIE were tested as potential covariates of pharmacokinetics of phenobarbital. Severe asphyxia was defined as pH of arterial umbilical cord blood ≤7.1 and Apgar 5 ≤5, and severe HIE was defined as time to normalization of amplitude-integrated electroencephalography (aEEG) >24 h. RESULTS: Weight was found to be the only statistically significant covariate for the volume of distribution. At weight of 1 kg volume of distribution was 0.91 L and for every additional kg it increased in 0.91 L. Clearance was 0.00563 L/h. No covariates were statistically significant for the clearance of phenobarbital. CONCLUSIONS: Phenobarbital dose adjustments are not indicated in the studied population, irrespective of the severity of asphyxia or HIE.
- MeSH
- asfyxie novorozenců * komplikace farmakoterapie MeSH
- asfyxie komplikace farmakoterapie MeSH
- dospělí MeSH
- fenobarbital farmakokinetika terapeutické užití MeSH
- lidé MeSH
- mozková hypoxie a ischemie * terapie MeSH
- novorozenec MeSH
- terapeutická hypotermie * metody MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus contortus. This parasite is able to protect itself against ABZ via the formation of inactive ABZ-glycosides. The present study was designed to deepen the knowledge about the role of UDP-glycosyltransferases (UGTs) in ABZ glycosylation in H. contortus. The induction effect of phenobarbital, a classical inducer of UGTs, as well as ABZ and ABZ-sulphoxide (ABZSO, the main active metabolite of ABZ) on UGTs expression and UGT activity toward ABZ was studied ex vivo in isolated adult nematodes. The effect of three potential UGT inhibitors (5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine and sulfinpyrazone) on ABZ glycosylation was tested. Pre-incubation of nematodes with ABZ and ABZSO led to increased expression of several UGTs as well as ABZ-glycosides formation in subsequent treatment. Phenobarbital also induced UGTs expression, but did not affect ABZ biotransformation. In the nematode's subcellular fraction, sulfinpyrazone inhibited UGT activity toward ABZ, although no effect of other inhibitors was observed. The inhibitory potential of sulfinpyrazone on the formation of ABZ-glycosides was also proved ex vivo in living nematodes. The obtained results confirmed the role of UGTs in ABZ biotransformation in H. contortus adults and revealed sulfinpyrazone as a potent inhibitor of ABZ glycosylation in this parasite. The possible use of sulfinpyrazone with ABZ in combination therapy merits further research.
- MeSH
- albendazol MeSH
- anthelmintika * terapeutické užití MeSH
- fenobarbital metabolismus farmakologie terapeutické užití MeSH
- glykosidy metabolismus farmakologie terapeutické užití MeSH
- glykosyltransferasy MeSH
- Haemonchus * MeSH
- hlístice * MeSH
- nemoci ovcí * farmakoterapie MeSH
- ovce MeSH
- sulfinpyrazon metabolismus farmakologie terapeutické užití MeSH
- uridindifosfát MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Na úrovni farmakokinetiky jsou lékové interakce antiepileptik spojeny obvykle s enzymatickou indukcí nebo inhibicí. Méně časté jsou interakce v oblasti absorpce, vazby na plazmatické bílkoviny nebo renální exkrece. Farmakodynamické interakce antiepileptik s dalšími látkami se zřídka týkají synergismu s možností snížení dávek, spíše se zvyšuje incidence vedlejších účinků. Čistě farmakodynamické interakce byly popsány u oxcarbazepinu, perampanelu a pregabalinu.
Drug interactions of antiepileptic drugs are mostly connected with enzymatic induction or inhibition. The interaction on level of absorption, plasma-protein binding of renal excretion is less frequent. Pharmacodynamic interaction of antiepileptics with other drugs is seldom synergistic with a possibility of declination of dose. The increase of adverse drug reactions is more common. Purely pharmacodynamic interaction was described with oxcarbazepin, perampanel and pregabalin. The new antiepileptics have lower interaction potential - most of them are excreted either via kidney or extrahepatal (e. g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin). Enzymatic induction is either not present or minimal. The inductive effect is necessary to be taken into account in carbamazepine, phenytoin and phenobarbital. Inhibitive effect is held in valproic acid and felbamate. The interactive potential among newer antiepileptics is the highest in lamotrigine, oxcarbazepine and rufinamide. Drug interactions were not found in lacosamide, pregabalin, stiripentol and vigabatrin.
- MeSH
- antikonvulziva * farmakokinetika krev MeSH
- fenobarbital farmakokinetika MeSH
- fenytoin farmakokinetika MeSH
- gabapentin farmakokinetika MeSH
- karbamazepin farmakokinetika MeSH
- kyselina valproová farmakokinetika MeSH
- lamotrigin farmakokinetika MeSH
- lékové interakce * MeSH
- lidé MeSH
- primidon farmakokinetika MeSH
- topiramat farmakokinetika MeSH
- Check Tag
- lidé MeSH
Na úrovni farmakokinetiky jsou lékové interakce antiepileptik spojeny obvykle s enzymatickou indukcí nebo inhibicí. Méně časté jsou interakce v oblasti absorpce, vazby na plazmatické bílkoviny nebo renální exkrece. Farmakodynamické interakce antiepileptik s dalšími látkami se zřídka týkají synergismu s možností snížení dávek, spíše se zvyšuje incidence vedlejších účinků. Čistě farmakodynamické interakce byly popsány u oxcarbazepinu, perampanelu a pregabalinu. Nová antiepileptika mají nižší interakční potenciál - řada z nich se vylučuje renálně nebo extrahepatálně (např. gabapentin, lacosamid, levetiracetam, topiramát, vigabatrin). K enzymatické indukci pak nedochází vůbec nebo zcela minimálně. Ze starších látek lze počítat s projevem indukčního efektu u karbamazepinu, fenytoinu a fenobarbitalu. Inhibiční efekt se uplatňuje u valproátu a felbamátu. Z nových látek je interakční potenciál nejvyšší u lamotriginu, oxcarbazepinu a rufinamidu. Lékové interakce nebyly popsány u lacosamidu, pregabalinu, stiripentolu a vigabatrinu.
Drug interactions of antiepileptic drugs are mostly connected with enzymatic induction or inhibition. The interaction on level of absorption, plasma-protein binding of renal excretion is less frequent. Pharmacodynamic interaction of antiepileptics with other drugs is seldom synergistic with a possibility of declination of dose. The increase of adverse drug reactions is more common. Purely pharmacodynamic interaction was described with oxcarbazepin, perampanel and pregabalin. The new antiepileptics have lower interaction potential - most of them are excreted either via kidney or extrahepatal (e. g. gabapentin, lacosamide, levetiracetam, topiramate, vigabatrin). Enzymatic induction is either not present or minimal. The inductive effect is necessary to be taken into account in carbamazepine, phenytoin and phenobarbital. Inhibitive effect is held in valproic acid and felbamate. The interactive potential among newer antiepileptics is the highest in lamotrigine, oxcarbazepine and rufinamide. Drug interactions were not found in lacosamide, pregabalin, stiripentol and vigabatrin.
- MeSH
- antikonvulziva * farmakokinetika krev MeSH
- fenobarbital farmakokinetika MeSH
- fenytoin farmakokinetika MeSH
- gabapentin farmakokinetika MeSH
- karbamazepin farmakokinetika MeSH
- kyselina valproová farmakokinetika MeSH
- lamotrigin farmakokinetika MeSH
- lékové interakce * MeSH
- lidé MeSH
- primidon farmakokinetika MeSH
- topiramat farmakokinetika MeSH
- Check Tag
- lidé MeSH
Ibuprofen is one of the most widely used pharmaceuticals, and due to its inefficient removal by conventional wastewater treatment, it can be found in natural surface waters at high concentrations. Recently, we demonstrated that the TpBD-(CF3)2 covalent organic framework (COF) can adsorb ibuprofen from ultrapure water with high efficiency. Here, we investigate the performance of the COF for the extraction of ibuprofen from natural water samples from a lake, river, and estuary. In general, the complexity of the natural water matrix induced a reduction in the adsorption efficiency of ibuprofen as compared to ultrapure water. The best performance, with over 70% adsorption efficiency, was found in lake water, the sample which featured the lowest pH. According to the theoretical calculations, ibuprofen more favorably interacts with the COF pores in the protonated form, which could partially account for the enhanced adsorption efficiency found in lake water. In addition, we explored the effect of the presence of competing pharmaceuticals, namely, acetaminophen and phenobarbital, on the ibuprofen adsorption as binary mixtures. Acetaminophen and phenobarbital were adsorbed by TpBD-(CF3)2 with low efficiency and their presence led to an increase in ibuprofen adsorption in the binary mixtures. Overall, this study demonstrates that TpBD-(CF3)2 is an efficient adsorbent for the extraction of ibuprofen from natural waters as well.
OBJECTIVES: This study characterizes the changes in the pharmacokinetics of phenobarbital associated with extracorporeal membrane oxygenation treatment in neonates, to illustrate our findings and provide guidance on dosing. DESIGN: Retrospective pilot population pharmacokinetic analysis. SETTING: Neonatal ICU. PATIENTS: Thirteen critically ill neonates (birth body weight, 3.21 kg [2.65-3.72 kg]; postnatal age at start of treatment: 2 d [0-7 d]; gestational age: 38 wk [38-41 wk]) receiving venovenous or venoarterial extracorporeal membrane oxygenation. INTERVENTIONS: Phenobarbital administered in a loading dose of 7.5 mg/kg (8.5-16 mg/kg) and maintenance dose of 6.9 mg/kg/d (4.5-8.5 mg/kg/d). MEASUREMENTS AND MAIN RESULTS: Therapeutic drug monitoring data were available, yielding 5, 31, and 19 phenobarbital concentrations before, during, and after extracorporeal membrane oxygenation, respectively. Population pharmacokinetic analysis was performed using NONMEM 7.3.0 (ICON Development Solutions, Ellicott City, MD). Maturation functions for clearance and volume of distribution were obtained from literature. In a one-compartment model, clearance and volume of distribution for a typical neonate off extracorporeal membrane oxygenation and with a median birth body weight (3.21 kg) at median postnatal age (2 d) were 0.0096 L/hr (relative SE = 11%)) and 2.72 L (16%), respectively. During extracorporeal membrane oxygenation, clearance was found to linearly increase with time. Upon decannulation, phenobarbital clearance initially decreased and subsequently increased slowly driven by maturation. Extracorporeal membrane oxygenation-related changes in volume of distribution could not be identified, possibly due to sparse data collection shortly after extracorporeal membrane oxygenation start. According to the model, target attainment is achieved in the first 12 days of extracorporeal membrane oxygenation with a regimen of a loading dose of 20 mg/kg and a maintenance dose of 4 mg/kg/d divided in two doses with an increase of 0.25 mg/kg every 12 hours during extracorporeal membrane oxygenation treatment. CONCLUSIONS: We found a time-dependent increase in phenobarbital clearance during the first 12 days of extracorporeal membrane oxygenation treatment in neonates, which results in continuously decreasing phenobarbital exposure and increases the risk of therapeutic failure over time. Due to high unexplained variability, frequent and repeated therapeutic drug monitoring should be considered even with the model-derived regimen.
Cíl studie: Vyhodnotit vliv možných rizikových faktorů a biochemických parametrů na outcome novorozenců s hypoxicko-ischemickou encefalopatií II.–III. stupně (léčených řízenou hypotermií) ve 24 měsících věku. Metodika: V prospektivní studii byly u 51 novorozenců (gestační stáří 36 až 41) s hypoxicko-ischemickou encefalopatií II.–III. stupně, léčených řízenou hypotermií, sledovány rizikové faktory (místo narození, čas zahájení řízené hypotermie, porodní hmotnost, skóre podle Apgarové v 5. a 10. minutě života, výskyt křečí, sérová hodnota laktátu a laktátdehydrogenázy aj.). Ve 24 měsících věku byli pacienti rozděleni do 2 skupin podle výsledku léčby – outcome příznivý (adekvátní neurologický vývoj) a nepříznivý (závažné motorické nebo smyslové postižení, event. úmrtí). Poté byla v jednotlivých skupinách vyhodnocena závislost výsledku léčby na sledovaných rizikových parametrech. Výsledky: Sedm dětí v průběhu studie zemřelo. U přeživších 44 dětí byl ve věku dvou let shledán příznivý vývoj ve 34 případech, v 10 případech byl nález nepříznivý. Za rizikové faktory s nepříznivým vlivem na výsledek léčby byly označeny nízké Apgar skóre v 5. a 10. minutě, křeče rezistentní na léčbu, vstupní hodnoty pH, base excess, laktátu i laktátdehydrogenázy v arteriální krvi při příjmu pacienta. U novorozenců v průběhu řízené hypotermie sice nastal významný pokles hodnot laktátu v obou skupinách, nicméně mezi skupinami byl zřejmý, statisticky významný rozdíl v jeho aktuálně naměřených hodnotách. Závěr: Vyšší sérová hodnota laktátu, laktátdehydrogenázy v časném postasfyktickém období a křečová aktivita rezistentní na farmakoterapii u novorozenců s hypoxicko-ischemickou encefalopatií II.–III. stupně léčených řízenou hypotermií jsou spjaty s nepříznivým outcome.
Risk factors affecting the outcome of newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy Aim of the study: To evaluate the role of potential risk factors and biochemical parameters in the outcome, at 24 months of age, of newborns treated by therapeutic hypothermia for stage II and III hypoxic-ischemic encephalopathy. Material and methods: This prospective study comprised 51 newborns, of gestation age from 36–41 weeks, who were undergoing hypothermia treatment for stage II and III hypoxic-ischemic encephalopathy. Various risk factors were noted and monitored including birthplace, time hypothermia treatment was initiated, birth weight, Apgar score at 5 and 10 minutes of life, occurrence of seizures, serum lactate values, and lactate dehydrogenase. At 24 months, the patients were assessed and consequently divided into two groups. Patients placed in one group exhibited normal psychomotor development and were therefore judged to have positive treatment outcomes; the other group comprised those who displayed severely compromised motor coordination or sensory impairment, or even died. In each group specific risk factors were subsequently evaluated to determine their influence on treatment outcome. Results: Seven infants died during the course of the study. Of the remaining 44 examined at 2 years old, 34 exhibited positive psychomotor development, with adverse findings in 10 cases. The risk factors associated with adverse treatment outcome were noted to be low Apgar score at 5 and 10 minutes, seizures resistant to treatment, initial pH values, base excess, and lactate and lactate dehydrogenase in arterial blood at the time of admission. While both patient groups saw a significant reduction in lactate values over the course of hypothermia treatment, it was nevertheless clear that there were significant statistical differences in observed values. Conclusion: Elevated serum lactate values, lactate dehydrogenase early in the period post-asphyxia, and seizure activity resistant to pharmacotherapy are indicative of adverse outcomes in newborns receiving therapeutic hypothermia for stage II and III hypoxic-ischemic encephalopathy.
- MeSH
- antikonvulziva MeSH
- fenobarbital terapeutické užití MeSH
- kyselina mléčná analýza škodlivé účinky MeSH
- lidé MeSH
- mozková hypoxie a ischemie * diagnóza patologie MeSH
- nemoci novorozenců diagnóza MeSH
- novorozenec MeSH
- prospektivní studie MeSH
- rizikové faktory MeSH
- terapeutická hypotermie * MeSH
- výsledek těhotenství MeSH
- záchvaty farmakoterapie MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
