From Molecular Mechanisms to Clinical Evidences

Abstract

After more than a century from its discovery, valproic acid (VPA) still represents one of the most efficient antiepi-leptic drugs (AEDs). Pre and post-synaptic effects of VPA depend on a very broad spectrum of actions, including the regu-lation of ionic currents and the facilitation of GABAergic over glutamatergic transmission. As a result, VPA indirectly mod-ulates neurotransmitter release and strengthens the threshold for seizure activity. However, even though participating to the anticonvulsant action, such mechanisms seem to have minor impact on epileptogenesis. Nonetheless, VPA has been reported to exert anti-epileptogenic effects. Epigenetic mechanisms, including histone deacetylases (HDACs), BDNF and GDNF modulation are pivotal to orientate neurons toward a neuroprotective status and promote dendritic spines organization. From such broad spectrum of actions comes constantly enlarging indications for VPA. It represents a drug of choice in child and adult with epilepsy, with either general or focal seizures, and is a consistent and safe IV option in generalized convulsive sta-tus epilepticus. Moreover, since VPA modulates DNA transcription through HDACs, recent evidences point to its use as an anti-nociceptive in migraine prophylaxis, and, even more interestingly, as a positive modulator of chemotherapy in cancer treatment. Furthermore, VPA-induced neuroprotection is under investigation for benefit in stroke and traumatic brain injury. Hence, VPA has still got its place in epilepsy, and yet deserves attention for its use far beyond neurological diseases. In this review, we aim to highlight, with a translational intent, the molecular basis and the clinical indications of VPA.

Keywords: Valproic acid, epilepsy, epileptogenesis, neuroprotection, pharmacology, epigenetics

1. INTRODUCTION

Valproate was introduced in clinical practice about 50 years ago, and its efficacy and tolerability profiles have been well reported in preclinical and clinical settings. It is a mainstay of antiepileptic therapy because of a broad spectrum of effectiveness for a wide range of seizures and epileptic syndromes. Indeed, data from several clinical trials suggest that valproate has the broadest spectrum of anticonvulsant action compared to all currently available antiepileptic drugs (AEDs), both in adults and children suffering from epilepsy [1]. The aim of this review is to analyze both clinical
and preclinical aspects regarding the use of valproic acid
(N-dipropylacetic acid or VPA), moving from preclinical evidences of anticonvulsant activity and neuroprotection to clinical data on efficacy and tolerability profile both in the pediatric and adult population. We examined specific review articles, preclinical studies, systematic reviews, textbooks, meta-analysis, retrospective studies and evinced that because of a good compromise between multiple clinical uses and tolerability of side effects, beyond specific precautions in female of childbearing potential [2], VPA is a first choice drug to this day in the treatment of many epileptic and non-epileptic diseases, and still deserves attention for the implication of its epigenetic effect in several fields, from epileptogenesis to cancer treatment [3, 4] .

2. HISTORICAL BACKGROUND

VPA is a unique drug, and is to date one of the most prescribed AEDs worldwide. VPA is a branched short-chain fatty acid deriving from valeric acid, a low molecular weight carboxylic acid. In 1882, Beverley Burton, an American chemist, was the first to synthetize VPA, which was considered at first an organic solvent [5]. However, VPA antiepileptic property was discovered after more than 50 years, in 1962, when it was tested as a solvent for other molecules being checked for potential anticonvulsant activity [6]. After laboratory studies demonstrated its anticonvulsant activity, the first clinical trial using VPA in epilepsy was performed in 1964 [7]. The drug made its way to the European market under the brand Depakine in France in 1967, followed by the UK in 1973 and other European countries in the following decade. Being liquid, it is used as a coniugated sodium salt, constituting a water-soluble powder. After Food and Drug Administration (FDA) approval in 1978, it also became available in the US [8].

3. PHARMACOKINETICS AND PHARMACO-
DYNAMICS

The bioavailability of VPA ranges from 96 to 100% for all commonly used formulations, which include normal and sustained-release tablets, film-coated tablets, capsules and oral or intravenous solutions. VPA bioavailability is maintained during chronic treatment when its absorption is even quicker compared to absorption after a single dose. Absorption is consistently delayed if the drug is taken 2 to 3 hours after a meal, which explains why it tends to be significantly slower in the afternoon, after lunch, than in the morning, after breakfast. VPA highly binds to proteins (87-95%), resulting in low clearance rates (6-20 ml/h/Kg) [8]. However, protein binding depends on VPA concentration, so that if the serum level of VPA is above the therapeutic range (>600 µmol/L, 80 µg/mL), protein binding may decrease up to 67%. Some conditions, usually linked with hypoproteinemia, are likely to reduce VPA protein bound fraction: renal disease, liver disease, old age, pregnancy and use of other protein-bound drugs, depending on competitor’s affinity to plasma proteins. In human beings, VPA is metabolized via three major pathways: glucuronidation, beta-oxidation and cytochrome P450 (CYP)-mediated oxidation. The first two pathways are predominant, since they made up for 50% and 40% of the VPA metabolized respectively, while CYP dependent oxidation represents a minor route, managing less than 10% of VPA [9]. Valproate glucuronide is the principal metabolite of VPA in urine (30-50%), and is not considered to be toxic for cells. On the contrary, some of the products of VPA metabolism produced by mitochondrial and non-mitochondrial pathways are known to be hepatotoxic. Indeed, a pivotal step in VPA metabolism is the CYP2C9, 2A6 and 2B6 mediated production of 4-ene-VPA, toxic to cells. VPA half-life ranges from 9 to 18 hours, with shorter timings, from 5 to 12 hours, only observed with concomitant treatment with enzyme-inducing drugs, including phenytoine (PHT), carbamazepine (CBZ) and barbiturates [10]. VPA enhances γ aminobutyric acid (GABA) synthesis and release, leading to the potentiation of GABA-ergic transmission in specific brain regions [11]. At the same time, it also reduces the release of the excitatory molecules, such as β-hydroxybutyric acid, and reduces neuronal excitation due to the activation of N-metyl-D-aspartate (NMDA) glutamate receptors [12]. In addition to these properties, the anticonvulsant effect of VPA also derives from the attenuation of the high frequency neuronal firing, obtained via the blockade of voltage gated ionic channels, including sodium, potassium and calcium channels [13]. Results from preclinical and clinical studies also suggest that VPA modulates dopaminergic (DA-ergic) and serotoninergic (5HT-ergic) transmission, paramount for its effectiveness in psychiatric disorders, as well as in neurological disorders beyond epilepsy [14]. Recently VPA has been shown to inhibit the histone deacetylases (HDAC), especially HDAC1, potentially regulating the expression of genes participating in apoptosis and antitumor action. Thus, VPA has been proposed as a possible anticancer drug, able to boost the effects of chemotherapeutics [15]. VPA is unique among all AEDs for the wide spectrum of effectiveness against all the types of seizure and epileptic syndromes, both in pediatric and adult patients. In particular, it has been tested in both generalized (tonic-clonic, absences and myoclonic) and focal seizures, and it has been found effective in Lennox-Gastaut, West and Dravet syndrome Table (). The efficacy, safety and tolerability of intravenous (IV) VPA has also been evaluated in the management of generalized convulsive status epilepticus (GCSE) [16] Table (). VPA is a multitarget drug with strong antinociceptive and anti-inflammatory action at low dosages, with such effects deriving from the inhibition of the TNF-α related pathways. Hence, it is currently used in migraine prophylaxis as well as for the treatment of several psychiatric diseases, including bipolar and mood disorders [3, 17]. In the last decades, the neuroprotective effects of VPA have been reported in a broad variety of acute CNS injuries models, including stroke and hypoxia, traumatic brain injury and spinal cord injury [18].

Table 1

VPA monotherapy in epilepsy from 1978 to 2018.

4. MECHANISM OF ACTION AND EFFECTS IN EXPERIMENTAL MODELS

4.1. Effect on GABA and Glutamate Systems

During the last half century, a broad spectrum of mechanisms have been discovered to participate in the anti-epileptic, mood-stabilizer and neuroprotective properties of VPA. One of the main mechanisms of VPA concerns a pre and post-synaptic modulation of GABA-ergic transmission Fig. (). Specifically, VPA increases the inhibitory activity of gamma-aminobutyric acid (GABA) with both pre-synaptic and post-synaptic mechanisms, promoting the availability of synaptic GABA as well as facilitating GABA mediated responses [19]. Moreover, VPA directly acts on GABA receptors, enhancing the stimulus-induced responses of both GABA-A and GABA-B receptors [20]. In particular, through a direct interaction with the benzodiazepines regulatory regions of GABA receptors, VPA delays the extinction of the post-synaptic inhibitory potential due to the activation of GABA-A receptors, and also facilitates the tethering of baclofen to GABA-B receptors [11, 21, 14]. The selective enhancement of GABA-ergic mediated transmission explains the increase in brain GABA concentration under VPA treatment [22, 23]. Beyond influencing the inhibitory GABAergic system, VPA also modulates the transmission of excitatory aminoacids, such as glutamate. In rat models, VPA reduced the NMDA and kainate-induced excitatory responses within the medial prefrontal cortex [24]. Moreover, VPA increases the expression of NR2A and NR2B subunits of the NMDAR, promoting neural cortex neuroplasticity, though controlling excitotoxicity and apoptosis via the overexpression of associated calcium/calmodulin-dependent protein kinase II [25] Fig. (). Moreover, NR2A/2B expression regulation allows an indirect regulation of Ras-ERK pathway and glutamate receptor trafficking [26]. In mice with Bassoon gene (Bsn) mutation, with irregular neuronal activity and spontaneous persistent cortical seizures also associated with altered NR2A/2B ratio in NMDAR, VPA has been reported to rebalance NR2A/2B ratio, rescue striatal synaptic plasticity, and reduce seizures and mortality [27]. Moreover, the chronic administration of VPA reduced the hippocampal neurons surface expression and synaptic localization of GluR1/2 [28] Fig. ().

Valproate effects on synaptic cleft and intracellular pathways. The increase in GABAergic transmission pairs with a modulation other aminergic systems; the excitatory ionic channels, such as calcium and sodium channels, are negatively modulated, while potassium currents are enhanced. Moreover, epigenetic mechanisms influence receptor expression and neuroprotective pathways. Legend. AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid –AMPA- receptor; BDNF: brain derived neurotrophic factor; DA: dopamine; D2R: dopamine D2 receptor; GABA: gaba-amino-butirric acid; GABAR: GABA receptors; GABA-A: GABA receptor type A; GABA-B: GABA receptor type B; HSPs: heat shock proteins; HSP-70: heat shock protein 70; K⁺: potassium; IDO: indoleamine 2,3 dioxygenase; MAO-A: mono-amines oxidase type A; M-channel: low-threshold noninactivating voltage-gated potassium current; MMP-9: metalloproteinases-9; Na⁺ channel: sodium channel; NMDAR: N-metyl-D-aspartate -NMDA- receptor; NR2A: 2A subunit of NMDAR; NR2B: 2B subunit of NMDAR; Par-4: prostate apoptosis response-4; T-Ca⁺ channel: low-threshold T-calcium channel; TNF-α: tumor necrosis factor α; VPA: valproate; 5HT: serotonin.

4.2. Effect on Serotonin and Dopamine Systems

VPA has been shown to enhance the extracellular level of serotonin (5-HT) and dopamine (DA) in the hippocampus and striatum, even though this modulation seemed to be unrelated to the antiepileptic effect of VPA [29, 30]. On the contrary, VPA-induced modulation of the DA-ergic and serotoninergic systems was demonstrated relevant for the antipsychotic and neuropsychiatric actions of VPA. Moreover, VPA participates in DA signaling pathways via epigenetic mechanisms, increasing the transcription of the prostate apoptosis response-4 (Par-4) factor [31]. Since Par-4 positively modulates the intracellular DA D2 receptor (D2R) pathway [32], VPA indirectly enhances the activity of the D2R cascade [31]. Furthermore, VPA, activating the 5-HT1A receptors, increases DA-release in pre-frontal areas [1, 14, 30, 33] Fig. () and Table 2). Moreover, in animal models of depression, both up-regulation of 5-HT transporter and downregulation of monoamine oxidases type A (MAO-A) have been linked to the antidepressant action of VPA [34].

4.3. Effect on Ionic Channels

VPA action on neuronal firing is concentration and activity dependent. Indeed, VPA has been reported to limit high frequency repetitive firing in cultured neurons at concentrations much lower than those required to depress a normal neuronal cell activity [35]. This effect, critical for the anticonvulsant action of VPA, is linked to the modulation of sodium, calcium and potassium channels, especially with a use-dependent decrease in inward sodium currents [36]. Specifically, VPA blocks both persistent and fast sodium currents [37]. The limitation of persistent sodium channel-induced currents, being selective, confers VPA the property of protecting against seizures, at the same time having minimal interference with normal neuronal function [36]. In peripheral ganglion neurons, VPA has also been shown to block low threshold T calcium channels activity, acting on both pre and post-synaptic level [38]. Moreover, even though only achievable with high concentrations, VPA increases the amplitude of the late potassium outward currents, further increasing the threshold for epileptiform activity [39] Fig. (). However, it should be noted that the ion channel regulation seems not to have a crucial role in VPA-mediated neuroprotection against ischemic damage in in vitro setting [40] or in experimental epileptogenesis models [41]. Further challenging the role of ionic channel regulation as primary to VPA action, a recent experimental study, addressing membrane permeability in an animal-derived hippocampal epilepsy model, reported that VPA effects were unrelated to
the reduction in presynaptic sodium or calcium currents [42]. On the contrary, an anticonvulsant direct effect has been

postulated for the VPA-induced regulation of the M-channel, that generates a low-threshold voltage-gated potassium
current restoring neuron rest potential. The preservation of M-channel induced currents has thus been proposed as a possible therapeutic target for antiepileptic drugs, especially VPA [43].

4.4. Epigenetics Effects

Beyond the direct modulation of excitatory and inhibitory synaptic pathways, VPA also has long-term effects. Since VPA effects may take long timing to manifest and persist despite discontinuation, it is unarguable that some of them derive from a central action, the key of which is gene expression modulation [44]. Epigenetic mechanism of VPA is determinant to its several action, such as the anticonvulsant activity, the neuroprotective effects and the ability to modulate neurogenesis [27]. The term “epigenetic” stands for an information that can be inherited during or after cell division, without being strictly related to the DNA pure sequence. Thus, “epigenetic” refers to a heritable DNA accessory data, such as its methylation or histone acetylation status [45, 46]. This epigenetic mechanism leads to a long-lasting over-generation modification in gene expression, crucial to regulatory processes in central nervous system [46]. VPA long-term action counts on epigenetic mechanisms, such as those related to the transcription and regulation of synaptic receptors and several signaling molecules, with high impact on excitotoxic and neuroprotective pathways [44, 47]. Main pathways of VPA epigenetic effects depend on the inhibition of the histone deacetylase (HDAC) and the modulation of brain-derived neurotrophic factor (BDNF) [48] Fig. (). Indeed, VPA, via HDAC inhibition, modulates DNA demethylation and histone acetylation, resulting in a modification of nucleosome status and chromatin structure [9, 49, 50]. Chromatin decondensation is regulated by several associated proteins, such as Structural Maintenance of Chromatin proteins (SMC), SMC-associated proteins and DNA methyltransferases. With down-stream effects, VPA modulates all of these proteins, regulating the sensitivity of DNA to nucleases [44]. HDACs are divided into 4 classes, with VPA acting only on the first two [51]. DNA methylation, especially when it involves the “promoter” region, corresponds to the inhibition of gene transcription. The inhibition of HDACs leads to chromatin de-condensation and facilitation of DNA transcription. Thus, VPA, inhibiting HDACs, indirectly regulates gene expression [51]. Moreover, VPA can induce mono-, di- and tri-methylation on a lysine 9 region of histone3 (h4), with direct facilitation of transcriptional activity [52]. With different pathways, down-regulating SMCs, inhibiting HDACs and modulating h4 methylation, VPA consistently influences gene expression. VPA chronically enhances the interaction between the transcription factors, including c-Fos and c-Jun, and the activator protein 1 (AP-1), promoting the expression of AP-1 controlled genes [53, 54]. Moreover, AP-1 DNA binding is time and dose-dependently increased by VPA treatment [55]. Thus, VPA progressively furthers the transcription of AP-1 dependent genes, such as Bcl-2, serotonin-2A (5-HT2A) receptor and GAP-43 [55, 56]. Among all others transcription factors, VPA also modulates the CAMP response element-binding protein (CREB) and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). VPA influence on NF-kB leads to a modulation of the immune response via the decrease of TNF-alpha and IL-6 [57]. More tangled is to date the relationship between VPA and CREB, a transcription factor implicated in phosphorylation in neuronal development, migration, memory and synaptic plasticity [44, 58]. Contrasting results emerged from studies on animal models, in which VPA was shown to decrease the activity of NF-kB in the frontal cortex [59], while other authors described an increase in the hippocampus and cortex mediated by the ERK-pathway, with a subsequent increase in brain derived neurotrophic factor (BDNF) [44]. BDNF is a brain-specific signalling molecule pivotal for cell survival, growth and migration [60]. The expression of BDNF highly varies according to developmental stage [61, 62]. VPA modulation of BDNF expression has been matter of several controversies, mainly related to the differences in study paradigms and to the deduction of BDNF expression from the levels of its codifying mRNA. In particular, rats receiving VPA in the prenatal period were first shown to express high BDNF mRNA levels in the neural tube [54], while in vitro cortical neurons have been shown to have low BDNF transcript when exposed to VPA [62-64]. BDNF protein levels have been only recently investigated by ELISA in mice models, suggesting that early post-natal exposure to VPA reduces BDNF expression by nearly 50%. Moreover, VPA has been shown to preserve a region-specific pattern, decreasing BDNF expression in the cerebellum while not impacting on hippocampal BDNF protein level [62] Fig. (). As for BDNF, in vivo and in vitro researches showed VPA increases also the glial cell line-derived neurotrophic factor (GDNF), which takes part in the neuroprotective and cognitive-enhancer properties [44, 65]. The regulation of neuronal survival mediated by VPA also derives from the up-regulation of neuron-specific genes. In particular, VPA up-regulates NeuroD, a neuron-located transcription factor increasing the expression of genes promoting neuronal survival, such as Bad and Bcl-2, potentiating GABA-ergic transmission [44, 66]. What is more, VPA suppresses the transcription of both apoptotic (including Bax gene), and pro-inflammatory (such as IL6, Fas-L, and metalloproteinases) signals [67]. Epigenetic mechanisms also take part in the anticonvulsant action of VPA. Indeed, VPA has been reported to modulate the expression of SCN3A, a gene codifying for the α-isoform of the voltage-gated sodium channel III. This channel, that under normal circumstances presents only in the childhood [68], is overexpressed in epileptic patients and seizure animal models as well [9, 69]. SCN3A confers high neuronal excitability, thus it has been implicated in the development of epilepsy, and is considered as a target for interventions aimed at its down-regulation. Indeed, since methylation of SCN3A promoter critically regulates its transcription, it has been implicated in epileptogenesis too. VPA has been shown to downregulate SCN3A expression in a mice model, reducing the methylation of the gene promoter. Thus, VPA was suggested to achieve an anticonvulsant action also through epigenetic pathways based on the downregulation of SNCA3 expression [9]. Such properties are exclusive to VPA since no changes in SCN3A expression has been found with other anticonvulsants, such as CBZ or lamotrigine (LTG) [9]. VPA epigenetic pathways have been shown to participate in epileptogenesis. Antiepileptic drugs (AEDs) are very different one another both in terms of cellular mechanisms and in anticonvulsant activity and efficacy [42, 70]. Investigations both in seizure models and human beings have demonstrated that the anticonvulsant activity of AEDs could highly vary during prolonged treatment. For example, benzodiazepines efficacy decreases over time due to adaptive processes, mainly receptor modifications conferring “functional tolerance”. Older AEDs, such as phenobarbital (PB), can incur in metabolic tolerance, due to an adaptive remodeling of the enzymes deputed to drug elimination or metabolism [23, 70]. On the other side, some AEDs seem to increase their efficacy over time. If for some of them the mechanisms of such curious effect have been reported, such as for the tissue accumulation of PB in patients treated with primidone, for VPA no clear explanation has been proposed, even though epigenetic pathways and epileptogenesis modulation are crucial to it [23]. The term epileptogenesis refers to those artificial or spontaneous processes that lead to recurrent seizures. Stroke, traumatic brain injury, toxic insults and status epilepticus can all be the starting point of epileptogenesis [44, 71]. VPA has been shown to block seizure-induced neurogenesis, and such effect has been directly linked to the epigenetic mechanisms deriving from HDAC inhibition [48] (Table ). What is more, BDNF expression control is crucial to seizure control and, therein, to epileptogenesis [48, 72-74]. Indeed, BDNF transcription increases in the foci of seizures both in animal models and patients [72, 75]. Moreover, both in animal models and patients, epileptiform activity has been reported to result in a consistent long-term up-regulation of tyrosin kinase tropomyosin-related kinase B (TrkB), the intra-cellular receptor binding BDNF. The consistent facilitation of BDNF binding leads to the promotion of several pathways controlling
synaptic plasticity and neurite growth [48, 73, 74, 76, 77]. VPA role in influencing synaptic plasticity also derives
from the regulation of the BDNF/TrkB pathway. This
pathway has been shown to modulate striatal plasticity in the Bsn model, a mice model developing early-onset epilepsy. As soon as cortical seizures repeat, neuronal cells react
with a specific changes in their plasticity patterns, resulting in the facilitation of the feedforward inhibition within
the striatal circuitry [48]. TrkB/BDNF are crucial to the induction and preservation of the altered synaptic plasticity, which derives from a severe up-regulation of TrkB and an erroneous distribution of BDNF among fast-spiking interneurons and medium spiny neurons. VPA has been shown to restore the physiologic expression pattern of TrkB, and to promote the correct distribution of BDNF among striatal neurons. Thus, through seizure reduction and epigenetic mechanisms, VPA directly modulates synaptic plasticity [48] Fig. (), Table ).

Table 2

Effects of VPA in different animal models of epilepsy.

5. THERAPEUTICAL ASPECTS: FROM EXPERIMENTAL TO CLINICAL EVIDENCES

The development of new AEDs, with improved effectiveness and better tolerability profiles, represents to date the most important goal of neuropharmacology in epilepsy, and relies on preclinical research on animal models. Despite the availability of countless animal models of epileptic seizures and epilepsy, pharmacological studies are rarely performed on the few of the chronic models of epilepsy at our disposal Table () [14, 23]. These animal models can be categorized, according to the timing in which they present seizures, in acute or chronic seizures models. However, both categories include paradigms characterized by the induction of seizures or epilepsy using chemical or electrical stimuli in previously healthy and “non-epileptic” animals, mostly rats [41, 71, 78, 79].

5.1. Antiepileptic and Antiepileptogenic Effects

Experimental studies performed in various models of generalized and focal seizures have widely confirmed the antiepileptic effect of VPA [23, 80] Table (). Despite ineffective in preventing status epilepticus in a pilocarpine model [81, 82], VPA significantly increased the latency to seizure initiation [83, 84], although the observation period (72 hours) was too short to allow a thorough assessment of treatment effectiveness [84] Table (). In the pentylenetetrazol (PTZ) model of epilepsy [81, 85, 86], VPA acute intraperitoneal administration significantly increased the seizure threshold, with anticonvulsant activity further potentiated by prolonged treatment [87-89] Table (). The efficacy of VPA was confirmed also in the electroshock-induced seizures model (MES), where VPA dose-dependently reduced seizure frequency [90] Table (). In an experimental design, based on a kindling model [91, 92], VPA dose-dependently increased the number of after-discharges (AD) required to induce epileptic seizures [93] Table (). VPA decreased the AD duration and effectively prevented seizures regulating membrane permeability, blocking the voltage-dependent sodium channels and the T-type voltage-activated Ca²⁺ currents, and also potentiating GABA-mediated inhibition [94]. In the kindling model, VPA also counteracted the neuronal damage induced by prolonged seizures in the hippocampal formation, promoting neuroprotection and preventing the development of behavioral disturbances [80, 92]. Similar effects were reported in the kainate model of status epilepticus [95, 79], despite being not confirmed in the pilocarpine temporal lobe epilepsy (TLE) model [84] Table (). Moreover, in a rat model of human temporal lobe epilepsy (TLE), VPA efficiently decreased mean seizure frequency and was able to bring to a seizure-free status [96]. In the mouse epilepsy model derived from the manipulation of the Bsn gene, characterized by frequent seizures but long survival [97, 98], VPA significantly reduced seizure frequency and mortality [99] Table (). Nevertheless, despite suppressing seizures, the vast majority of AEDs is unable to limit the course of the underlying natural history of epilepsy. Thus, even though critical to seizure control, AEDs still lack a clear anti-epileptogenic potential [100]. Among all AEDs, though several have shown neuroprotective properties, only few have been reported to have anti-epileptogenic effects [101]. Indeed, data from the kindling pharmacoresistant epilepsy model, suggest that VPA prevents kindling development and blocks fully kindled seizures, thus acting both as a symptomatic as well as disease-modifying drug [93, 94] Table (). The fine regulation of glutamatergic and GABAergic pathway and the neuroprotective properties of VPA are crucial to the modulation of epileptogenesis [101, 102]. In particular, epileptic seizures, especially status epilepticus (SE), can produce neuronal damage, and, later on, recurrent spontaneous seizure activity [101, 103]. Thus, the inhibition of neuronal damage, through neuroprotective mechanisms, represents a possible strategy to prevent epileptogenesis [104]. VPA has been widely investigated for its broad spectrum of effects peculiar to this indication. In the kainic acid model of SE, high doses of VPA for 40 days after SE induction, beyond protecting hippocampal neurons from seizure-induced damage, also inhibited following spontaneous activity [95]. Moreover, VPA exposure was associated with prevention of seizure induced cognitive impairment, highlighting the critical role of neuroprotection for both processes [95]. In the same setting, however, PB was ineffective in achieving both neuroprotection and antiepileptogenesis [95]. Even though neuroprotective effects were also provided with gabapentin, other AEDs, such as PB and levetiracetam (LEV), failed to reproduce the effects of VPA, with spontaneous seizure activity and behavioral deficit happening despite high dosages respectively in the kainic acid and amygdala electrical stimulation models [95, 105] Table (). Further experimental evidences supporting VPA anti-epileptogenic effects derive from different SE models. In particular, in an SE model induced by a sustained electrical stimulation of the basolateral amygdala, VPA was reported to be as effective as a selective blocker of AMPA receptor subtype in preventing neuronal loss. Specific, VPA 24 hours continuous infusion after the end of electrical stimulation significantly provided neuronal hippocampal neuroprotection, comparable to an anti-excitotoxic and glutamate depleting agent such as NS1209 (8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo [3,2-h]-iso-quinoline-2,3-dione-3-O-(4-hydroxybutyric acid-2-yl)oxime) [106]. Moreover, VPA efficacy has also been shown in a recently developed model of primary generalized seizure, obtained with repeated exposure to flurothyl, a GABA-A receptor antagonist. In this model, characterized by the generalized seizures that remit within 1 month from onset, VPA suppressed spontaneous seizures, blocking the evolution to more complex seizure types, further suggesting an inhibition of epileptogenetic processes [107]. Nevertheless, reports of VPA poor efficacy in preventing epileptogenesis render the issue still matter of debate. In 4 hours sustained SE rat model, achieved with electrical stimulation of amygdala, 4 weeks VPA treatment, even though preventing hippocampal neurodegeneration, did not significantly reduce spontaneous seizure activity [108] Table (). VPA has also been shown ineffective in preventing further seizures in a pilocarpine-induced SE model [84]. However, poor homogeneity among experimental protocols seems a major issue to overcome to critically assess VPA effects. To date, an educated guess aroused as to whether the timing of VPA treatment might consistently influence epileptogenesis, with some authors suggesting a pivotal role of early VPA exposure to obtain significant neuroprotective effects [101]. Further studies with appropriately designed experimental protocols are needed to shed light on VPA effects and their time-dependence.

5.2. Neuroprotection from Neuronal Damage

“Neuroprotection” refers to the biochemically induced resources to prevent, resist or cope with a specific neuronal hazard. Pathways of neuroprotection can derive from clinical, structural, electrical and molecular cellular changes. Despite the huge research interest in the last decades, we still need to define the neuroprotective role of VPA with well-implemented clinical trials, translating the results of the experimental findings, often providing conflicting results, in the clinical field. The neuroprotective role of VPA in ischemic hazard has been reported to depend on the modulation of HDAC after hypoxic insults [40, 109-112]. Nonetheless, several pathways have been shown to take part in VPA-induced neuroprotection [113]. In rodent models of ischemic middle cerebral artery occlusion (MCAO), VPA produced an HDAC inhibition-mediated suppression of NF-kB and metalloproteinase-9 activation, leading to attenuated post-ischemic brain-blood barrier disruption and reduced brain edema [111, 114]. Furthermore, in the same MCAO model, VPA also reduced the infarct size and the clinical deficit via the up-regulation of heat-shock proteins, especially Hsp-70, and the suppression of caspase-3 expression and activation [114, 115]. The increase in Hsp-70 was also reported in the alternative model of animal brain ischemia, the four-vessel occlusion, together with a decrease in IL-1β and TNF-α, and the upregulation of gelsolin [114, 116, 117]. Evidences from in vitro study on ischemic insults also suggest VPA is highly neuroprotective. Specifically, in an in vitro model of oxygen and glucose deprivation, patch-clamp recording highlighted the protection from in vitro ischemia conferred by VPA treatment [40]. However, contrarily to CBZ and TPM, able to provide neuroprotection through the simultaneous limitation of fast sodium and high-voltage activated calcium channels, VPA reaches a significant neuroprotection at higher doses, and independently from ionic channels regulation, suggesting a prevalent role of intracellular mechanism, such as the regulation of caspases activity [40, 115]. A further pathway, involving microglia, has been implicated in VPA-induced neuroprotection [118]. Neuronal cells cultured in organotypic hippocampal slices (OHSC) have been demonstrated to be consistently affected by N-methyl-D-aspartate (NMDA) induced excitotoxicity [119, 120]. The depletion of microglia enhanced neuronal cell death, especially in dentate gyrus and CA3 region of hippocampal slices, thus proposing microglia to be determinant in neuroprotection [120]. In ischemic and toxic insults, as well as in epilepsy, neuronal death is due to the release of 5’-triphosphate (ATP) in the extracellular space from the heavily activated neurons [121]. VPA has been shown to upregulate the ATP-activated purine receptor P2X7, leading, in microglia, to the release of tumor necrosis factor α (TNF α), boosting the neuroprotective pathway [118]. Thus, even though it still remains to be clarified if such effects depend on HDACs inhibition or DNA demethylation, VPA has been shown to act also on microglia to deliver its neuroprotective effects [118].

Beyond epilepsy and toxic/ischemic insults, VPA-mediated neuroprotection has been widely reported in several animal models of neurodegenerative disorders. Indeed, VPA exerted neuroprotection in a Parkinson’s disease rat model obtained with ventral tegmental area and substantia nigra (SN) injury [122-124]. In this recently developed animal model of Parkinson’s disease, motor and cognitive features result from neuronal loss due to the effects of lactalysin, an irreversible ubiquitin proteasome system (UPS) inhibitor. Lactalysin causes intracytoplasmic accumulation of altered proteins, especially alpha-synuclein, leading to degeneration of both DA-ergic and non-DA-ergic neurons in the SN pars compacta (SNpc) [124]. Alpha-synuclein has been shown to prevent the acetylation of histone proteins, and an imbalance of HDACs and histone acetyltransferase (HATs), the other enzyme deputed to the regulation of histone protein acetylation, has been shown in neurodegenerative diseases [125]. Thus, HDACs have been implicated in Parkinson’s disease [124]. In particular, since HDACs are expressed in the SNpc, VPA has been investigated to assess if, inhibiting HDACs, it could confer neuroprotection. In the lactolysin rat model, the neuronal loss produced by the injection of the irreversible proteasome inhibitor was dose-dependently counteracted with VPA treatment, mainly via the upregulation of neurotrophic factors [123, 124]. Moreover, neuroprotection was not only exerted in the SNpc, but also in the ventral tegmental area [122-124]. Hence, VPA represents a prime line candidate for intra-nigral and extra-nigral neuroprotection [124]. VPA neuroprotective properties are not exclusive to Parkinson’s disease, but have been reported in several other neurodegenerative conditions and models, from Huntington’s disease to amyloid beta-peptide induced neurotoxicity and amyotrophic lateral sclerosis [126, 127]. Regarding the latter, in an ALS animal model, VPA was able to reduce the expression of Homer1b/c, modulating apoptosis and neuronal loss and promoting neuronal protection and survival [128]. Further studies are on the verge of assessing the clinical benefit of VPA use as a neuroprotective agent in humans.

5.3. Cognitive Impairment and Autism Spectrum
Disorders

The association between epileptic activity and cognitive function has been highly debated in the last decades [129]. Epigenetic pathways have been implicated also in VPA antidepressant effect, as well as in the modifications in cognitive function. In particular, VPA has been reported to inhibit the expression of indoleamine 2,3 dioxygenase (IDO), modulating the kynurenine pathway of tryptophan metabolism [130, 34]. Nonetheless, the complex epigenetic cascade induced by VPA implies long-term beneficial as well as detrimental effects on neuronal homeostasis and plasticity [99, 131]. Bsn mutants mice have been often used as models, since the defective long-lasting synaptic plasticity in hippocampus, in particular in CA1 area, results in morphological alterations leading to hippocampal learning deficit. In this model, the treatment with VPA rescued physiologic LTP but was unable to restore either the morphological alterations of dendritic spines or the impairment of non-spatial hippocampal memory [99]. Sgobio and colleagues demonstrated that, in control animals, VPA treatment, when started early and longitudinally maintained, produced alterations in morphology of dendritic spines as well as impaired socially transmitted food preference. Such effects have been proposed as a possible explanation for cognitive dysfunction observed in children taking VPA [2, 99]. Both in vivo and in vitro models of epilepsy have confirmed dendritic morphology alterations, including spine loss, in the brain foci of seizures [132]. In epilepsy experimental models, alterations in dendritic morphology in the hippocampus (as well as in other brain areas) have been associated to memory deficits, which can be prevented controlling seizures [132-135]. Thus, hippocampal glutamate transport has been proposed as a possible future target for specifically designed drugs. Interestingly, chronic treatment with VPA leads to a dose-dependent increase in the hippocampal glutamate uptake, with an up-regulation of glutamate specific transporters [136]. Neuroprotection from glutamate induced excitotoxicity has been reported both in vivo and in vitro in several models of glutamatergic injury [126, 137]. In the Bsn mutant mice, the mutation of Bsn gene brings to the lack of a presynaptic structural protein, resulting in morphological alterations involving the pyramidal CA1 hippocampal neurons, including reduced dendrite length and branch nodes, as well as lower spine density on both apical and basal dendrites. VPA is unable to directly restore the original dendritic architecture but rescues the hippocampal synaptic plasticity, which participates in the epilepsy-induced memory deficits [99, 138]. This action, together with the facilitation of mitogen-activated protein kinases pathway, the modulation of neurogenesis and the blockade of cognitive decline induced by hippocampal seizure activity, have all been reported with VPA [139, 140]. In particular, VPA induced HDACs modulation results in inhibited neurogenesis in animal models of status epilepticus, preventing cognitive decline [140]. Positive cognitive effects were found in KA model, were treatment with VPA was superior to other AEDs in preserving spatial learning and memory function, which were evaluated through the modified Morris water-maze swim task [141]. However, in an animal study using the same Morris water-maze swim test paradigm, VPA failed to improve the cognitive performances of rats [108]. On the contrary, in an animal study using the novel object locating test to evaluate hippocampal driven spatial memory, a link between VPA and cognitive deficits has been postulated due to the suppression of hippocampal neurogenesis [142]. Beyond animal models, cognitive deficit was also addressed by studies on human beings, where prospective studies consistently documented that VPA is associated with an increased risk of cognitive impairment in young children, and of in utero malformations [2, 20, 143-147]. In particular, the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study reported cognitive impact in children after fetal VPA exposure. Specific, in children of mothers treated with VPA monotherapy, a dose-dependent negative VPA impact was found for several cognitive tests, including IQ, verbal and non-verbal abilities, memory, and executive function [148]. Similar results were also confirmed by further studies, which pointed at VPA as the main factor influencing children IQ, even more than maternal IQ [149]. Following studies further provided evidences for VPA-induced cognitive impairment [133, 150-153]. Moreover, heading back to animal models, even though several risk factors might participate in the process, fetal exposure to VPA during the first trimester of pregnancy resulted in higher incidence of autism in the offspring [153, 154]. Epigenetic mechanisms have also been proposed as the basis of VPA-induced autism spectrum disorders (ASD). VPA exposed animals have become one of the most widely used models of ASD. In such model, ASD-like behavior, with impaired sociability and marble burying, persisted in the following generations when VPA treated animals were mated with naïve females to produce second and third generation [131]. Such effect derives from a transgenerational inheritance of epigenetic modifications. Indeed, VPA impacts on DNA transcription with epigenetic mechanisms, leading to an increased susceptibility of transmitting new traits to the subsequent generations [131]. Since ASD-like behavior has been linked to an imbalance between glutamatergic and GABAergic transmission, experimental models have been tested to investigate whether a modulation of these systems can provide clinical benefit. In particular, very recently, a single treatment of agmatine, an endogenous NMDA receptor antagonist, has been shown to resolve ASD-like behaviour in the VPA model. Thus, agmatine and NMDA receptor agonists have been proposed as targets to restore ERK1/2 activation and resolve ASD-like behaviour [155]. Considered all the provided evidences, the United States Food and Drug Administration and the European Medicines Agency recently revised the indication of VPA treatment, especially in female patients [156-158]. To date, VPA use has been consistently restricted according to the results of retrospective and prospective studies suggesting VPA as a risk factor for ASD and cognitive impairment
[2, 146, 147]. Combining the data from these studies with further clinical evidences will help us to define the real weight of the effects of VPA on different stages of neurodevelopment.

5.4. Clinical Efficacy in Epilepsy

VPA is one of the most useful anticonvulsant drugs, and has one of the broadest profile of antiepileptic actions, as well as clinical indications. In fact, its efficacy in both focal and generalised seizures and epilepsy syndromes, especially in paediatric population, has been widely and accurately validated with randomised controlled trials and observational studies [159, 160]. Considering all available evidences, VPA stands out from other existing AEDs for its wide spectrum of activity against almost all seizure types. However, supporting evidences and clinical efficacy vary depending on different epilepsy syndromes. Since the late 1960s and early 1970s VPA has been used in many clinical trials proving its effectiveness in reducing the incidence of both generalized and focal seizures Table (). Several clinical trials consistently validated the high efficacy of VPA in patients suffering from typical and atypical absence seizures both in childhood and adulthood, showing similar seizure control using VPA or other AEDs [161-164]. In a recent review, Glauser and colleagues [165] showed that, in children suffering from newly diagnosed or untreated absence seizures, VPA initial monotherapy led to satisfactory seizure control, or seizure freedom without intolerable side effects Table (). Ethosuximide (ESM) and VPA have level A recommendation, while LTG has level C recommendation, for being used as initial monotherapy in newly diagnosed or untreated absence seizure in childhood. To date, the lack of data and the inconclusive ones deriving from the only ad-hoc phase III placebo-controlled trial do not allow us to recommend LEV for absence seizures, even though further studies might pave the way for the implementation of this drug in the near future [165, 166]. Recently, a Cochrane review tried to assess the evidence, deriving from placebo-controlled or drug-versus-drug controlled trials, supporting the effectiveness of ESM, VPA and LTG in treating absence seizures in children and adolescents [167]. Even though absence seizures are considered a relatively common seizure type among children, the authors identified only eight randomised controlled trials to be considered for analysis [165, 168-174], seven of them recruiting 20 to 48 participants. Only one study [165] included a much larger sample. This was a randomised, parallel double-blind controlled trial comparing ESM, LTG and VPA in children receiving a new diagnosis of absence epilepsy. A total of 453 previously untreated patients with typical absence seizure, between seven months and 12 years, were enrolled and followed up to 12 months. The review found some evidence, based on the eight small trials previously mentioned, suggesting that LTG treatment was more likely to result in seizure free status compared with placebo treatment. At the same time, these authors found clear evidence that patients taking ESM or VPA experienced significantly higher seizure free rates compared to patients taking LTG. However, considered the different adverse event profiles of the two drugs, ESM is preferred over VPA in children with absence epilepsy. Nevertheless, it must be underlined that if absence and generalised tonic-clonic seizures co-exist, VPA should be preferred [159]. In 1982 Turnbull and colleagues [175] found that treatment with PHT or VPA achieved a satisfactory control of both primary generalized tonic-clonic seizures (PGTC) and focal seizures, reporting however a lower effectiveness in the control of the latter ones Table (). Such results were replicated in further studies with the achievement of a good seizure control through therapeutic levels of VPA Table () [176]. The “Standard and New Antiepileptic Drugs- SANAD study”, an unblinded randomized controlled trial performed in 2007 in the United Kingdom (UK) [177], estimated and confronted the efficacy and tolerability profile of VPA, LTG and topiramate (TPM) in generalized and unclassified epilepsy Table (). In accordance with previous observations, these authors suggested that VPA represents the first line treatment for the majority of patients diagnosed with idiopathic generalized epilepsy or unclassifiable seizures, while LTG and TPM should be avoided because of lower effectiveness and tolerability profiles [177]. This study was criticized a few months later because the lack of blinding might have affected the time to treatment failure and because based on a non-prescriptive protocol allowing clinicians to decide drug dosages according to patient’s clinical conditions. Therefore we believe that the SANAD study was extremely useful to describe the drugs characteristics but it is necessary to analyze the longer term outcomes that are important in chronic diseases such as epilepsy. In a multicenter double-blind trial [178] that compared VPA versus CBZ in the treatment of adults with complex partial seizures (CPS) or secondarily generalized tonic-clonic seizures (SGTC), VPA and CBZ had similar efficacy profiles, even though a better control of CPS was achieved with CBZ Table (). In conclusion, VPA should be considered a first-choice drug for the treatment of generalised onset seizures in adulthood, and its wide spectrum of efficacy recommends its use in several types of epilepsy, even in seizures difficult to classify. Further studies demonstrated VPA efficacy in refractory focal epilepsy, supporting its prescription as a very first-line AEDs to treat scarcely responsive patients [179] Table (). A series of studies over the past years reported that convulsive and non-convulsive status epilepticus (SE) could be treated with intravenous (IV) VPA in young children [160]. This offered an advantage over more sedating agents, which could cause hypotension or respiratory depression. However, the limited number of available studies regarding the use of VPA in SE and their poor quality makes it difficult to obtain implications for clinical practice. More rigorous randomized controlled trials (RCTs) comparing VPA with other AEDs electively used in SE are needed to state its efficacy and tolerability in clinical practice. In addition VPA is efficient in rare syndromes including West syndrome, Lennox-Gastaut syndrome, myoclonic or myoclonic astatic seizures, absences, myoclonic idiopathic generalized epilepsies, generalized tonic-clonic seizures precipitated by photic stimulation, and in Dravet syndrome [180]. In some children with narrow photosensitivity ranges, preventive measures might avoid seizure onset, whereas in patients with severe photosensitivity, drug treatment is often mandatory. Covanis et al. suggested that VPA could be the first-line drug for photosensitivity associated epilepsies since 85% of patients reach seizure free status under VPA treatment [181] Table (). Finally, it is important to underline that, in comparison to other AEDs (e.g. CBZ), VPA seems to possess little potential to worsen seizures. Indeed, only anecdotal reports highlighting seizure worsening with VPA are available in literature, with a reason for paradoxical effect of VPA remaining largely unclear [182]. In the last decades, thanks to the variety of mechanisms of action, VPA is gaining attention as a possible treatment for several conditions other than epilepsy. Recently, the U.S. Food and Drug Administration and the European Medicines Agency (FDA/EMA) approved VPA use for the treatment of bipolar disorders and for migraine prophylaxis, and it might also have potential implications in Alzheimer’s disease and in cancer therapy, especially for its epigenetic effects [47].

5.5. Clinical Efficacy in Cancer Treatment

Great interest has aroused in the last decades regarding the possible role of VPA as an adjunct treatment for solid tumours. Several evidences suggest VPA use as a treatment “booster” in several type of cancer. Preclinical data report anticancer effect of VPA over 20 solid tumours, from melanoma to colon cancer cells, and evidences seem to accumulate year after year [4]. In particular, in animal models, VPA, modulating the transcription of genes such as ABCA1, ABCA3 or ABCA7, increased the sensitivity to cisplatin among non-small cell lung cancer cells [183]. VPA epigenetic effects have been implied in the treatment of breast cancer, where, in the near future, its use as an HDAC inhibitors could be combined with chemotherapy to target oncogenes through different pathways [184]. The same aim recently aroused also for squamous cells neoplasms [185]. Moreover, VPA can increase the efficacy of radiotherapy in patients with glioblastoma, and, at the same time, to protect hippocampal neurons from radiotherapy induced sugranular zone apoptosis, preventing cognitive deficit associated with brain irradiation [186]. Quite the opposite, no benefit for glioblastoma treatment was achieved associating VPA with best medical therapy (chemotherapy) in a pooled cohort of patients diagnosed with glioblastoma, deriving from four randomized clinical trials [187]. Further clinical studies are needed in order to define VPA efficacy as an adjunct treatment for solid cancer.

6. MAIN ADVERSE EFFECTS

Although VPA is generally well-tolerated and has a favorable tolerability profile, its use might be limited by reduction in efficacy or by the onset of adverse drug reactions (ADR) [2, 10, 188]. Overall, compared to older and newer AEDs, central nervous system-related ADRs are usually rare; in fact, VPA is not generally associated with drowsiness and fatigability with loss of concentration, and also the detrimental effects on cognition are rare. Moreover, when compared to patients with migraine, epileptic patients seem to present ADRs of antiepileptic drugs, including VPA, far more rarely. In addition, when compared to LTG or TPM, VPA had significantly lower rates of ADRs among epileptic patients [189]. Many systematic reviews, clinical trials and post marketing literature reviews have evaluated the real extent of VPA side effects and their clinical implications including hepatic, gastrointestinal, neurological, hematological, cutaneous, teratogenic and metabolic disorders. The incidence of hepatotoxicity is <1% per 20.000 patients treated with VPA. However, hepatotoxicity is clearly age-dependent: its risk is indeed significantly higher (1:600- 1:800) in children below the age of 2 years, especially if suffering from severe seizure disorders or other neurological diseases, including brain damage and cognitive impairment [190]. Hepatotoxicity usually occurs within the first 6 months from VPA treatment initiation. Liver function tests can be carried out before the beginning of therapy, but often these evaluations are not useful because liver enzymes abnormalities do not always precede hepatotoxicity onset. Therefore, VPA is contraindicated in all conditions exposing to higher risk of hepatotoxicity, in particular in case of coexistence of metabolic disorders, including beta-oxidation or urea cycle impairment, and mitochondrial diseases, such as Leigh-syndrome, mitochondrial encephalopathy lactacidosis and stroke-like episodes, Alpers-Huttenlocher syndrome, ataxia-neuropathy spectrum, myoclonic epilepsy, myopathy and sensory ataxia and myoclonic epilepsy with ragged-red fibers [191, 192]. Clinical features of liver toxicity include apathy, somnolence or altered mental status, anorexia, vomiting, jaundice and possibly seizure worsening, especially during febrile status. Typical signs of VPA-induced hyperammonemic encephalopathy, that can rarely be fatal, are acute consciousness impairment, confusion, somnolence or lethargy, focal or bilateral neurological symptoms or signs as well as seizure worsening [193, 194]. Clinical picture can eventually progress towards severe ataxia, stupor and coma. Neurobehavioral alterations can be erroneously attributed to postictal effects, psychiatric disturbances or non-convulsive status epilepticus, leading to inappropriate increase in VPA dosages [195, 196]. Hyperammoniemic state can also be achieved with iv valproate administration [197]. In case the clinical picture raises the suspicion of urea cycle enzymatic defect, metabolic screening should be performed well in advance of starting VPA treatment [198]. In a recent randomized controlled clinical trial of newly diagnosed childhood absence epilepsy, VPA therapy was discontinued mostly because of its neurological, behavioral and psychiatric adverse effects [165]. Postural tremor is another adverse event of valproate, and often mimics essential tremor [10]. No definite relationship has been demonstrated between VPA dose and the onset of tremor, with observational data suggesting an increased prevalence of this adverse events among women [199]. Dizziness, memory problems, insomnia and nystagmus have been reported as common side effects that generally resolve with drug dose adjustments or discontinuation [200]. Headache, confusion, drowsiness, and tiredness have also been described with VPA [201] whereas delirium and dementia have been reported in a few case reports [202]. Gastrointestinal disturbances are relatively common in patients receiving VPA, with most frequently reported symptoms including nausea and vomiting, dysphagia and diarrhea [202, 203]. Abdominal pain and tenderness, independently from abdominal distension, vomiting, diarrhea, lethargy and apathy must be considered as alarm signs for possible pancreatitis, in particular in the pediatric population. Hence, screening with sensitive blood tests such as serum amylase is recommended, as well as dosage of serum lipases, more sensitive and lasting at elevated levels for prolonged time [204, 205]. This important and severe adverse effect develops generally within the first months of therapy, especially in young children, more often if treated with multiple therapies. Although no individual predisposition to VPA hematologic toxicity has been identified, a wide spectrum of hematologic abnormalities have been reported during this treatment ranging from transient immune thrombocytopenia to isolated neutropenia, red cell aplasia and bone marrow failure [206-210]. Hypersensitivity syndrome reactions (HSR) represent very rare idiosyncratic ADRs which can develop independently from dosage, timing, frequency, posology, but can depend on host peculiar conditions [200, 211]. Clinical manifestations of this rare and severe syndrome include fever, skin rash and multiple organ involvement, in particular liver impairment and nephritis. Even rarer adverse events are hair loss and hair texture alterations, which usually occur in the first month of treatment to find a spontaneous resolution in following months, gait disturbances [212], delirium [213], and parkinsonism [214].

6.1. Weight Changes and Endocrine Disturbances

Weight gain represents a possible adverse event of VPA and, being often marked, actually impacts on patient quality of life [215]. Despite being extremely heterogeneous among patients taking VPA, it is clear that in female patients, which are more prone to develop it especially during puberty [216], it can be frequent and disturbing, with significant detrimental effect on therapy compliance and quality of life. Moreover, sometimes the increase in weight can itself limit the prescription of VPA in clinical practice [217, 218]. Indeed, among adolescent girls, excessive weight gain can cause serious psychological disturbances as well as facilitate the development of important endocrinological abnormalities [219]. The mechanism through which VPA may induce an increase in body weight is still debated. However, among the several proposed hypotheses, the most supported are a dysregulation of the hypothalamic system, the effects on adipokine levels [220], hyperinsulinaemia and the increase in insulin resistance [196]. Many studies show a strict relationship between weight gain, hyperinsulinemia and insulin resistance during treatment with VPA both in children and adults [221-228]. Overall, several studies report an association between hyperinsulinaemia, dyslipidemia, obesity, especially visceral one, and insulin resistance. The onset of hyperinsulinaemia among obese patients taking VPA does not depend only on the development of insulin resistance after body weight increase and obesity. On the contrary, insulin resistance itself, once developed, might lead to weight gain, with visceral fat further facilitating insulin resistance closing a vicious circle. Indeed, VPA induced weight gain correlates with an increase in insulin, but with decreased glycemia able to foster appetite, and eventually, worsen weight gain itself [229]. Moreover, epigenetic mechanisms also participate in weight gain, with VPA inducing the transcription of genes coding for fat mass and obesity-associated (FTO) proteins, highly related to fat mass increase [9]. Nevertheless, the overexpression of FTO modulates the acetylation of SCN3A, reducing its expression; thus, FTO mediates weight gain as well as VPA anticonvulsant action [9]. Even though VPA probably is not able to provoke direct insulin secretion, it might still limit insulin hepatic metabolism, resulting in prolonged hyperinsulinaemia [196]. Thus, in VPA patients with obesity, hyperinsulinemia, insulin resistance and weight gain all participate maintaining one another {Lihn, 2005 #488} [230]. Moreover, a serious clinical condition related to weight gain, insulin resistance and hyperinsulinemia is metabolic syndrome, including atherogenic dyslipidemia and elevated blood pressure [196, 231]. Despite data are still lacking regarding the exact frequency of these adverse events, hyperandrogenism, menstrual irregularities, and polycystic ovary syndrome have all been related to the chronic use of VPA [232]. In particular, an increased prevalence of polycystic ovaries (PCO), hyperandrogenism and menstrual irregularities such adverse events are significantly more commonly reported among women receiving VPA compared to those receiving other AEDs [233]. In addition, anti-progestin action of VPA might also contribute to the higher frequency of anovulatory cycles [217]. Reproductive and sexual endocrine disorders can occur also in males treated with VPA. In male patients reproductive disorders have scarcely been analyzed. Altered sperm mobility, reduced testicular weight and infertility are possible reproductive disorders [234].

6.2. Pregnancy and Teratogenic Risk

VPA can cross the placenta and can cause a spectrum of congenital abnormalities. The vast majority of congenital malformations in children born from epileptic women receiving VPA during pregnancy seems to be due to the direct teratogenic effects of VPA rather than to the epileptic disorder affecting the mother [235]. Teratogenic effects are much higher when VPA is given as a co-medication with other anticonvulsants. The most frequent reported effects are neural tube or cardiovascular defects, orofacial cleft, hypospadia, atresia of the gastrointestinal tract, diaphragmatic hernia and craniosynostosis [200, 236]. For all these reasons, in 2014 the European Medicines Agency restricted the use of VPA in women and girls of childbearing potential, “unless other treatments are ineffective or not tolerated” [158]. In fact, the exposure to VPA in the prenatal period is associated with major congenital malformation. The large case-control study based on data collected from the “European Surveillance of Congenital Anomalies database” reported a consistent correlation between first trimester exposure to VPA monotherapy and augmented risk for spina bifida, craniosynostosis, cleft palate, hypospadia, atrial septal defect and polydactyly [237]. Similarly, a meta-analysis conducted in 2005 revealed that, compared to other commonly used AEDs, VPA prenatal exposure was associated with a 2 to 7 fold increase in the risk of major congenital malformations, including neural tube and cardiovascular defects, genitourinary or musculoskeletal abnormalities, and cleft lip or palate [238, 239]. A dose-dependent increase in the risk of teratogenic effects related to VPA exposure during pregnancy has been suggested according to data derived from both prospective cohort studies and national birth registers [146, 147, 240]. Results from the North American AED Pregnancy Registry, including pregnant women, enrolled between 1997

and 2011, pointed to a dose-dependent increase in risk of malformations with VPA and PB compared to lamotrigine and levetiracetam [241]. Recently, Tomson and colleagues have provided evidences from a large observational registry (EURAP) regarding teratogenic risk with eight different antiepileptic drugs [242]. Data from the largest prospective cohort study of pregnancies in women with epilepsy (EURAP registry) confirmed that the use of VPA is dose-dependently associated with an increased risk of congenital malformations at 1 year after birth. However, the study also allowed comparison between different antiepileptic drugs and dose regimens. From such comparison emerged that low dosage of valproate (≤650 mg/day) carried a risk of congenital malformations similar to high-dose carbamazepine (>700 mg/day) and lamotrigine (>325 mg/day) [242]. Overall, in women of childbearing potential, as well as in pregnancy, monotherapy with low doses of levetiracetam or lamotrigine seems the most appropriate choice to date.

Beyond the recommendations available in women of childbearing potential, specific attention should be paid for off-label use of VPA. Indeed, VPA is also used outside of the typical indications, with a potential risk of minor surveillance on the potential risk on both short and long-term [243].

Valproic Acid: MedlinePlus Drug Information

Valproic acid may cause serious or life-threatening damage to the liver that is most likely to occur within the first 6 months of therapy. The risk of developing liver damage is greater in children who are younger than 2 years of age and are also taking more than one medication to prevent seizures, have certain inherited diseases that may prevent the body from changing food to energy normally, or any condition that affects the ability to think, learn, and understand. Tell your doctor if you have a certain inherited condition that affects the brain, muscles, nerves, and liver (Alpers Huttenlocher Syndrome), urea cycle disorder (an inherited condition that affects the ability to metabolize protein), or liver disease. Your doctor will probably tell you not to take valproic acid. If you notice that your seizures are more severe or happen more often or if you experience any of the following symptoms, call your doctor immediately: excessive tiredness, lack of energy, weakness, pain on the right side of your stomach, loss of appetite, nausea, vomiting,, dark urine, yellowing of your skin or the whites of your eyes, or swelling of the face.

Valproic acid can cause serious birth defects (physical problems that are present at birth), especially affecting the brain and spinal cord and can also cause lower intelligence and problems with movement and coordination, learning, communication, emotions, and behavior in babies exposed to valproic acid before birth. Tell your doctor if you are pregnant or plan to become pregnant. Women who are pregnant or who are able to become pregnant and are not using effective birth control must not take valproic acid to prevent migraine headaches. Women who are pregnant should only take valproic acid to treat seizures or bipolar disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods) if other medications have not successfully controlled their symptoms or cannot be used. Talk to your doctor about the risks of using valproic acid during pregnancy. If you are a woman of childbearing age, including girls from the start of puberty, talk to your doctor about using other possible treatments instead of valproic acid. If the decision is made to use valproic acid, you must use effective birth control during your treatment. Talk to your doctor about birth control methods that will work for you. If you become pregnant while taking valproic acid, call your doctor immediately. Valproic acid can harm the fetus.

Valproic acid may cause serious or life-threatening damage to the pancreas. This may occur at any time during your treatment. If you experience any of the following symptoms, call your doctor immediately: ongoing pain that begins in the stomach area but may spread to the back nausea, vomiting, or loss of appetite.

Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your response to valproic acid.

Talk to your doctor about the risks of taking valproic acid or of giving valproic acid to your child.

Your doctor or pharmacist will give you the manufacturer’s patient information sheet (Medication Guide) when you begin treatment with valproic acid and each time you refill your prescription. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer’s website to obtain the Medication Guide.

Types, Uses, Effects, and More

For 70% of patients with epilepsy, drugs can control seizures. However, they can’t cure epilepsy, and most people will need to continue taking medications.

An accurate diagnosis of the type of epilepsy (not just the type of seizure, because most seizure types occur in different types of epilepsy) a person has is very important in choosing the best treatment. The type of medication prescribed will also depend on several factors specific to each patient, such as which side effects can be tolerated, other illnesses they may have, and which delivery method is acceptable.

Below is a list of some of the most common brand-name drugs currently used to treat epilepsy. Your doctor may prefer that you take the brand name of anticonvulsant and not the generic substitution. Talk with your doctor about this important issue.

Brivaracetam (Briviact)

• Approved for use as an add-on treatment to other medications in treating partial onset seizures in patients age 16 years and older.
• Possible side effects include drowsiness, dizziness, fatigue, nausea and vomiting.

Cannabidiol (Epidiolex)

• Approved in 2018 for treatment of severe or hard-to-treat seizures including those in patients with Lennox-Gastaut syndrome and Dravet syndrome.
• Common side effects include lethargy, sleepiness, fatigue, increased appetite, diarrhea and sleep disorders.

Carbamazepine (Carbatrol or Tegretol)

• For partial, generalized tonic-clonic and mixed seizures
• Common adverse effects include fatigue, vision changes, nausea, dizziness, rash.

Cenobamate (Xcopri)

• For use in adults with partial onset seizures
• Common side effects include insomnia, dizziness, fatigue, diplopia, and headache were most common in trials

Diazepam (Valium), lorazepam (Ativan) and similar Benzodiazepine tranquilizers such as clonazepam (Klonopin)

• Effective in short-term treatment of all seizures; used often in the emergency room to stop a seizure, particularly status epilepticus
• Tolerance develops in most within a few weeks, so the same dose has less effect over time.
• Valium can be given orallly, as an injection, in an IV or as rectal suppository.
• Side effects include tiredness, unsteady walking, nausea, depression, and loss of appetite. In children, they can cause drooling and hyperactivity.

Eslicarbazepine (Aptiom)

• This drug is a once-a-day medication used alone or in combination with other anti-seizure drugs to treat partial-onset seizures.
• The most common side effects include dizziness, nausea, headache, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor.

Ethosuximide (Zarontin)

• Used to treat absence seizures
• Adverse effects include nausea, vomiting, decreased appetite, and weight loss.

Felbamate (Felbatol)

• Treats partial seizures alone and some partial and generalized seizures in Lennox-Gastaut Syndrome; is used rarely and only when no other medications have been effective.
• Side effects include decreased appetite, weight loss, inability to sleep, headache, and depression. Although rare, the drug may cause bone marrow or liver failure. Therefore, the use of the drug is limited and patients taking it must have blood cell counts and liver tests regularly during therapy.

Fenfluramine (Fintepla)

• Schedule IV drug approved for treatment seizures in patients 2 and older who have Dravet syndrome.
• Common side effects include lose of appetite, vomiting, lethargy, problems with coordination including standing or walking, increased blood pressure, drooling, diarrhea, constipatipation.

Lacosamide (VIMPAT)

• This drug is approved to treat partial-onset seizures in adults with epilepsy.
• VIMPAT can be used alone or with other drugs.
• The drug comes as tablets, an oral solution, or injection.
• Side effects include dizziness, headache, and nausea.

Lamotrigine (Lamictal)

• Treats partial, some generalized seizures and mixed seizures.
• Has few side effects, but rarely people report dizziness, insomnia, or the potentially deadly Stevens Johnson rash.

Levetiracetam (Keppra)

• It is combined with other epilepsy drugs to treat partial seizures, primary generalized seizures and myoclonic (shock-like jerks of muscle) seizures.
• Side effects include tiredness, weakness, and behavioral changes.

Oxcarbazepine (Oxtellar XR, Trileptal)

• Used to treat partial seizures, it is a once-daily medicine used alone or with other medications to control seizures.
• Common side effects include dizziness, sleepiness, headache, vomiting, double vision, and balance problems.

Perampanel (Fycompa)

• The drug is approved to treat partial onset seizures and primary generalized tonic-clonic seizures in those age 12 and older.
• The label carries a warning of potential serious events including irritability, aggression, anger, anxiety, paranoia, euphoric mood, agitation, and changes in mental status.

Phenobarbitol

• Oldest epilepsy medicine still in use. It is used to treat most forms of seizures and is known for its effectiveness and low cost.
• Side effects can be sleepiness or changes in behavior.

Phenytoin (Dilantin)

• Controls partial seizures and generalized tonic-clonic seizures; also can be given by vein (intravenously) in the hospital to rapidly control active seizures, although if the drug is being delivered by IV, fosphenytoin (Cerebyx) is usually used.
• Side effects include dizziness, fatigue, slurred speech, acne, rash, gum thickening, and increased hair (hirsutism). Over the long term, the drug can cause bone thinning.

Pregabalin (Lyrica)

• Used with other epilepsy drugs to treat partial seizures, but is used more often to treat neuropathic pain.
• Side effects include dizziness, sleepiness (somnolence), dry mouth, peripheral edema, blurred vision, weight gain, and difficulty with concentration/attention.

Tiagabine (Gabitril)

• Used with other epilepsy drugs to treat partial seizures with or without generalized seizures
• Common side effects include dizziness, fatigue, weakness, irritability, anxiety, and confusion.

Topiramate (Topamax)

• Used with other drugs to treat partial or generalized tonic-clonic seizures. It is also used with absence seizures.
• Side effects include sleepiness, dizziness, speech problems, nervousness, memory problems, visions problems, weight loss.

Valproate, valproic acid (Depakene, Depakote)

• Used to treat partial, absence, and generalized tonic-clonic seizures
• Common side effects include dizziness, nausea, vomiting, tremor, hair loss, weight gain, depression in adults, irritability in children, reduced attention, a decrease in thinking speed. Over the long term, the drug can cause bone thinning, swelling of the ankles, irregular menstrual periods. More rare and dangerous effects include hearing loss, liver damage, decreased platelets (clotting cells), and pancreas problems.
• Should not be taken if pregnant.

Zonisamide (Zonegran)

• Used with other drugs to treat partial, generalized and myoclonic seizures
• Adverse effects include drowsiness, dizziness, unsteady gait, kidney stones, abdominal discomfort, headache, and rash.

Epilepsy Drug Guidelines

It may take several months before the best drug and dosage are determined for you. During this adjustment period, you will be carefully monitored through frequent blood tests to measure your response to the medication.

It is very important to keep your follow-up appointments with your doctor and the lab to minimize your risk for serious side effects and prevent complications.

When seizures continue despite treatment for epilepsy, it may be because the episodes thought to be seizures are non-epileptic. In such cases, you should get a second opinion from a specialist and have EEG-video monitoring so the diagnosis can be re-evaluated.

In specialized centers, about 15% to 20% of patients referred for persistent seizures that defy treatment ultimately prove to have non-epileptic conditions.

Valproic Acid (Depakene) – Side Effects, Interactions, Uses, Dosage, Warnings

You should not use valproic acid if you are allergic to it, or if you have:

• liver disease;
• a urea cycle disorder; or
• a genetic mitochondrial (MYE-toe-KON-dree-al) disorder such as Alpers’ disease or Alpers-Huttenlocher syndrome, especially in a child younger than 2 years old.

Valproic acid can cause liver failure that may be fatal, especially in children under age 2 and in people with liver problems caused by a genetic mitochondrial disorder.

Tell your doctor if you have ever had:

• liver problems caused by a genetic mitochondrial disorder;
• depression, mental illness, or suicidal thoughts or actions;
• a family history of a urea cycle disorder or infant deaths with unknown cause; or
• HIV or CMV (cytomegalovirus) infection.

Some young people have thoughts about suicide when first taking valproic acid. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Using valproic acid during pregnancy may increase the risk of serious birth defects that can develop early in pregnancy, even before you know you are pregnant. Using this medicine during pregnancy can also affect cognitive ability (reasoning, intelligence, problem-solving) later in your child’s life. However, having a seizure during pregnancy could harm both the mother and the baby.

If you take valproic acid for seizures or manic episodes: The benefit of preventing these conditions may outweigh any risks posed by this medicine. There may be other medications that are safer to use during pregnancy. Do not start or stop taking valproic acid without your doctor’s advice.

Do not use valproic acid to prevent migraine headaches if you are pregnant or you could become pregnant.

If you are not pregnant, use effective birth control to prevent pregnancy while using valproic acid. Tell your doctor if you start or stop using hormonal contraception that contains estrogen (birth control pills, injections, implants, skin patches, and vaginal rings). Estrogen can interact with valproic acid and make it less effective in preventing seizures.

It may not be safe to breastfeed while using this medicine. Ask your doctor about any risk.

Sodium Valproate – an overview

Nervous system

Sedation, fatigue, dizziness, headache, ataxia, and insomnia are less frequent with valproate than with other anticonvulsants. However, encephalopathy, sometimes associated with hyperammonemia and/or liver failure, has been described on several occasions, with symptoms ranging from acute confusion to stupor and even deep coma [40]. The stupor tends to be associated with bilaterally synchronous high-voltage, slow-wave EEG activity. Psychiatric symptoms and increased seizure frequency can also occur. Although in some cases valproate-induced stupor can be associated with increased epileptiform activity, it appeared to be triggered by a cortical non-epileptic mechanism in six patients who developed negative myoclonus and stupor after taking valproate for a few days [41].

A 45-year-old man with a 10-year history of post-traumatic stress disorder and alcoholism started stuttering after taking divalproex sodium 600 mg/day for 4 days [42].

When a 25-year-old woman with a hypothalamic hamartoma was given valproate (up to 2500 mg/day) in addition to phenytoin and phenobarbital, she became increasingly somnolent and spike and wave activity in her electroencephalogram deteriorated to the point when she appeared to be in absence status [43]. Her blood ammonia concentration was about three times the upper limit of the reference range. During wakefulness, electroencephalographic paroxysms increased with increasing plasma valproic acid concentrations and resolved (together with mental status changes and hyperammonemia) when valproate was withdrawn. The data are suggestive of a paradoxical effect of valproic acid on spike and wave activity, possibly related to the underlying pathology or hyperammonemia.

An unusual adverse reaction, uncontrollable laughter, was reported in two men aged 17 and 20 years [44]. The laughter persisted for 4–6 hours after an intravenous injection of 800 mg valproate over 1 hour.

Valproate rarely causes severe mental deterioration and CT/MRI findings suggestive of cortical atrophy, reversible after withdrawal [45]. Two possible additional cases have been reported in women with juvenile myoclonic epilepsy aged 22 and 46 years [46]. In one case mental function and brain atrophy regressed over a few months after stopping valproate, while in the other cognitive function improved but CT/MRI abnormalities persisted. The authors suggested that valproate-induced pseudoatrophy of the brain may not be always fully reversible, especially when the interval between onset of the condition and diagnosis is prolonged (2 years in this case). However, the possibility exists that the persistent cortical atrophy had other causes in their patient.

Retrospective studies have suggested that anticonvulsants may be associated with peripheral nerve dysfunction. This has been studied prospectively in 81 patients (aged 13–67 years) without polyneuropathy who took sodium valproate (n = 44) or carbamazepine (n = 37) as monotherapy in standard daily doses [47]. After 2 years one patient had clinical signs of polyneuropathy and six patients had symptoms of polyneuropathy, but electrophysiology did not show significant changes or trends. Only one patient had abnormal electrophysiological findings, which were only subclinical, and eight patients had abnormal values at two subsequent visits. There were no consistent patterns, and the data were unaffected when the drugs were examined separately or when patients were grouped according to whether or not they had symptoms of polyneuropathy. The authors concluded that previously untreated young to middle-aged patients who take valproic acid or carbamazepine for 2 years are not at risk of polyneuropathy.

Valproate can cause altered visual evoked potentials and brainstem evoked potentials [48]. In 100 epileptic patients aged 8–18 years taking valproate in a modified-release formulation, interpeak latencies of I-III and III-V of brainstem evoked potentials were significantly delayed and N75/P100 and P100/N145 amplitudes in the visual evoked potentials were reduced.

Valproate toxicity has been reported to have caused a neurodegenerative condition that mimicked multisystem atrophy in a 67-year-old woman [49].

In one report of 36 adults chronically treated with valproate at a veterans’ clinic, intellectual deterioration, sleep disorders, sexual dysfunction, personality changes, hearing difficulties, gait instability, tremor, parkinsonism, bradykinesia, abulia, and upper motor neuron signs were found in a large proportion, but selection bias was likely [50]. The severity of symptoms and signs varied from minimal to a degree that could lead to diagnosis of Parkinson’s disease or dementia. Improvement followed valproate withdrawal, and in two patients retested by CT scan cerebral atrophy regressed after drug withdrawal.

The regularity and maximum frequency of repetitive hand and finger movements and a simple reaction time test have been studied in 14 controls and 15 patients with epilepsy taking chronic valproate monotherapy and no subjective complaints related to motor function [51]. Repetitive hand and finger movements were significantly more irregular and the maximum frequency of repetitive movements was significantly lower in those taking valproate.

The effects of lithium and valproate on the risk of being involved in traffic accidents have been studied using three population-based registries [52]. Exposure consisted of receiving prescriptions for either lithium or valproate. Standardized incidence ratios were calculated by comparing the incidence of motor vehicle accidents during time exposed with the incidence during the time not exposed. During the study period, more than 20 000 road accidents occurred, including 36 during exposure to lithium and 31 during exposure to valproate. The overall risk of an accident was not increased, with the exception of a three-fold increase in risk among younger female drivers taking lithium.

Seizures

Valproate can occasionally cause aggravation of absence seizures in children [53]. Eight patients with typical and myoclonic absence epilepsy and electroencephalography that showed generalized 3-Hz spike-and-wave had an increase in the frequency of absence seizures within days of valproate introduction. Dosage increments resulted in further aggravation. Serum concentrations of valproate were in the target range in all cases. All the children improved on valproate withdrawal; in five valproate was reintroduced, resulting in further seizure aggravation. A 3-year-old girl had paradoxical worsening of seizures when the dosage of valproate was increased, with a dramatic increase in diffuse spike-waves during sleep and the emergence of myoclonic seizures; there was marked improvement after withdrawal of valproate and introduction of carbamazepine [54]. There was no evidence of encephalitis, valproate overdose, or metabolic abnormalities. Hyperglycinemia has been associated with paradoxical worsening of seizures.

Encephalopathy

There have been several further reports of valproate-induced hyperammonemic encephalopathy [55–58]. In one case it was associated with central pontine myelinolysis and coma in a patient with Sjögren’s syndrome who had taken long-term valproic acid for a psychotic disorder [59].

Encephalopathy has been studied in 63 adults who had taken valproate for a minimum of at least 2 years in a retrospective analysis [60]. Long duration of valproate treatment did not correlate with the risk of encephalopathy. In seven cases, temporary administration of lactulose alone was effective and valproate was not withdrawn. The authors also concluded that this complication is relatively common.

In one patient there was a possible synergistic interaction of valproic acid and topiramate with respect to the emergence of hyperammonemic encephalopathy [61]. The authors speculated that inhibition of carbonic anhydrase by topiramate might be the basis of this, since HCO⁻ is used in the synthesis of carbamoylphosphate in the urea cycle.

In a young child valproate-induced stupor was unusually associated with an electroencephalographic pattern of increased fast activity [62]. The authors speculated that this effect of valproate was related to an interaction of valproate with GABA metabolism and GABA neuronal networks.

Parkinsonism

Parkinsonism has been attributed to valproate [63–65], in one case associated with cognitive impairment [66]. Involuntary movements and twitching of the face and limbs have been also reported.

One patient with Huntington’s disease developed both parkinsonism and Pisa syndrome secondary to valproic acid [67]. Pisa syndrome is an uncommon type of truncal dystonia manifested by persistent lateral flexion of the trunk.

•

A 67-year-old man with Huntington’s disease (CAG expanded repeat of 41 triplets) and clear symptoms of the disease (hypotonia, dysarthria, generalized chorea, facial grimacing, slow saccadic eye movements, and impaired cognitive functions) was initially given olanzapine 10 mg/day, sertraline 50 mg/day, and clonazepam 1 mg/day, followed by valproic acid 500 mg bd because of progression of the cognitive impairment and psychiatric symptoms. Some days later, he developed worsening of gait impairment and a resting tremor in both arms, mild bilateral rigidity, marked bradykinesia, and anterior and right flexion of the trunk. Valproic acid was withdrawn and 1 week later his trunk posture improved dramatically, the right flexion disappeared, and he was able to walk without aid. His parkinsonian symptoms improved slightly and completely resolved within 2 months.

In a systematic review, 13 cases of parkinsonism associated with valproate were found; there was a variable time interval for the development of parkinsonism and most cases improved on withdrawal of the drug, but the rate and extent of improvement were unpredictable [68].

Reversible dementia with parkinsonism has been attributed to valproate [69]. In one patient, a 70-year-old woman, this complication was associated with systemic lupus erythematosus [70].

Tremor

Tremor is seen in 15% of patients taking valproate [71], although its incidence can increase to over 60% at serum drug concentrations in a high range (80–150 μg/ml) [72]; it is clinically reminiscent of essential tremor and responds to dosage reduction. Asterixis has been associated with intoxication by most anticonvulsants, but with valproate it can occur at therapeutic drug concentrations [73].

Chorea

Hemichorea has been attributed to high doses of valproate in a 53-year-old man with hemiparesis [74]. Intermittent choreiform movements were observed in two girls and one man, all with pre-existing severe brain damage, after they had taken valproate for 27 years [75]. Acute chorea has been attributed to valproate during an increase in dosage in an elderly woman, followed by resolution after withdrawal [76].

Valproic Acid – MotherToBaby

This sheet talks about using valproic acid in a pregnancy and while breastfeeding. This information should not take the place of medical care and advice from your healthcare provider.

What is valproic acid?

Valproic acid is a medication that has been used to control seizures in the treatment of epilepsy, and to treat bipolar disorder and migraines. Some brand names for valproic acid are Depakene®, Stavzor®, and Depacon®.

I take valproic acid. Can it make it harder for me to become pregnant?

Studies have found that women with seizure disorders and women with bipolar disorder might have menstrual problems and difficulty getting pregnant. This possible increase may be due to the conditions that the women have, rather than to the use of the medication.

I am taking valproic acid, but I would like to stop taking it before becoming pregnant. How long will valproic acid stay in my body?

People eliminate medications at different rates. In healthy adults, it takes 2-3 days, on average, for most of the valproic acid to be gone from the body.

I just found out that I am pregnant, should I stop taking valproic acid?

Talk with your healthcare providers before making any changes to this medication.  The possible benefits of taking valproic acid to treat your specific condition must be weighed against the possible risks to the pregnancy and the baby. Women who are taking valproic acid and are planning a pregnancy or could become pregnant should discuss their treatment options with their healthcare provider before becoming pregnant.

Does taking valproic acid increase the chance for miscarriage?

Miscarriage can occur in any pregnancy. There is not a known increased chance for miscarriage with the use of valproic acid during pregnancy. The maternal condition that the woman is taking the medication for may have a small increased chance for miscarriage.

What could happen to my baby if I stopped taking my valproic acid and then had a seizure during my pregnancy?

Having a seizure while pregnant may be harmful to the baby. Complications for your baby depend on many things, such as the type of seizure, how long the seizure lasts, and the number of seizures that happen. Epileptic seizures might cause periods of time when the baby is not getting enough oxygen, which could lead to problems with development. These seizures could also be life-threatening for both mother and baby. A seizure could cause a mother to fall or have an accident that could injure herself or her baby.

What could happen to my baby if I stopped taking my valproic acid and then had a relapse of bipolar disorder during my pregnancy?

Women with bipolar disorder who stop taking medication during their pregnancy may be at an increased risk for episodes of depression or mania that could be harmful to both the mother and the baby. Recurrence of depression or mania is very stressful for a pregnant woman. During mania or depressive episodes, the pregnant woman may have more trouble taking care of herself and keeping herself safe.

Does taking valproic acid in the first trimester increase the chance of birth defects?

In every pregnancy, a woman starts out with a 3-5% chance of having a baby with a birth defect. This is called her background risk. Studies have found that women who take valproic acid have a greater chance of having a baby with a major birth defect. Birth defects are typically classified as major if they need surgery to be repaired. The chance of a birth defect seems to be greater with higher doses of valproic acid or with taking more than one seizure medication. Some of the birth defects that are more likely to happen if a woman takes valproic acid in the first trimester are heart defects, cleft lip (lip develops with a split), or a neural tube defect (an opening in the baby’s spine or skull). Some babies exposed to valproic acid may also have more minor birth defects like facial differences, such as a thin upper lip.

The most common neural tube defect associated with valproic acid is spina bifida (opening in spine). The chance of a neural tube defect when taking valproic acid is approximately 1in 50 to 1in 100 (1-2%) Taking extra folic acid before trying to get pregnant and continuing in early pregnancy might help reduce the chance of some birth defects in pregnancies exposed to valproic acid. Talk to your healthcare provider about how much folic acid you should take. For more information on folic acid, please see the MotherToBaby fact sheet at: https://mothertobaby.org/fact-sheets/folic-acid/.

Could taking valproic acid in the second or third trimester cause other pregnancy complications?

Some, but not all, of the women taking valproic acid may have a smaller baby (below six pounds at birth). There have been reports of temporary low blood sugar levels (hypoglycemia), and some temporary behavior changes in the newborns.

Does taking valproic acid in pregnancy cause long-term problems in behavior or learning for the baby?

An increased chance for behavior and learning problems has been seen in babies who were exposed to valproic acid during pregnancy. Different studies have shown an increased chance for developmental delay, decreased language and memory skills, and decreased social and adaptive behavior skills. Not all studies have shown the same results, and some of the long term problems in the exposed children may be due to the severity of the seizure disorders in the pregnant woman during pregnancy.

I have been taking valproic acid for the last few years and I just found out I am pregnant. What tests are available to see if my baby has spina bifida or other birth defects?

Prenatal screening for neural tube defects is available in pregnancy. A blood test can be done to measure the amount of a substance called alpha fetoprotein (AFP) in the mother’s blood. Babies with spina bifida have higher levels of AFP. If the AFP is higher than usual in the blood test, more testing/screening may be offered to you to determine if the baby has birth defects.

An ultrasound that looks at the baby’s spine can be used to screen for spina bifida. Ultrasounds can also screen for some other birth defects, such as a heart defect or cleft lip. All of these prenatal screening/testing options can be discussed with your healthcare provider. There are no tests available during a pregnancy that can tell if there has been any effect on behavior or ability to learn.

Can I breastfeed while taking valproic acid?

Valproic acid is passed into breast milk, but has been measured at low or undetectable levels and seems to be compatible with breastfeeding. There is concern that breastfed infants whose mothers are taking valproic acid are at risk for liver toxicity, so the infants should be monitored for any changes or problems. If you suspect the baby has symptoms such as jaundice (yellowing of the skin or eyes), rash, or fever, contact the child’s healthcare provider. Talk to your healthcare provider about all of your breastfeeding questions.

If a man takes valproic acid, could it affect his fertility (ability to get partner pregnant) or increase the risk of birth defects?

Valproic acid may have effects on sperm shape and movement that could make it harder to get pregnant. There are no studies that look at paternal effects on pregnancy while taking valproic acid. In general, exposures that fathers have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/pdf/.

Please click here to view references.

OTIS/MotherToBaby recognizes that not all people identify as “men” or “women.” When using the term “mother,” we mean the source of the egg and/or uterus and by “father,” we mean the source of the sperm, regardless of the person’s gender identity.

View PDF Fact Sheet

007260: Valproic Acid, Serum or Plasma

Hepatotoxicity may be fatal, but is idiosyncratic and not preventable by routinely monitoring liver enzymes. Hepatotoxicity occurs in very young children, most often those on multiple anticonvulsants.¹ Valproate-induced cytopenias may be dose-related and warrant monitoring of complete blood counts during therapy.² Encephalopathy with hyperammonemia without liver function test abnormalities may occur.³ Pregnant women in first month are at risk for neural tube defects.

Valproate is absorbed rapidly and completely following oral administration; peak plasma concentrations usually occur within two hours after ingestion of liquid preparations and three to four hours after ingestion of the delayed-release tablet preparation, divalproex sodium, which contains sodium valproate and valproic acid. Food delays absorption but does not affect bioavailability.

The plasma protein binding of valproate is saturable within the usual therapeutic range (approximately 90% at 75 μg/mL). Usual effective plasma concentrations range from 50−120 μg/mL.⁴ With a daily dose of more than 500 mg, plasma concentrations may not increase proportionately because clearance increases with an increase in the free fraction. Daily fluctuations (up to two times higher) in free fraction and clearance also occur as a result of displacement by free fatty acids or circadian influences; thus, when plasma concentrations are being monitored, samples should be taken at a uniform time. Many neurologists recommend measuring trough concentrations.

Valproate is eliminated almost exclusively by hepatic metabolism. The metabolic fate is complex. A variety of conjugation and oxidative processes are involved, including entry into pathways (eg, beta oxidation) normally reserved for endogenous fatty acids. As the dose is increased, mitochondrial beta oxidation becomes saturated and increased glucuronidation occurs.

Metabolites may contribute to both antiepileptic and hepatotoxic effects. The antiepileptic activity of valproate (including the time course) is poorly correlated with steady-state valproate plasma concentrations. One unsaturated metabolite, 2-n-propyl-4-pentenoic acid (4-ene-VPA), has been proposed as a key hepatotoxic metabolite. The formation of this metabolite is increased by concomitant use of phenytoin, phenobarbital, carbamazepine, and other drugs that induce cytochrome P450. Due to inhibition of the same enzyme system, valproic acid may cause elevated levels of clomipramine with resultant seizures when the two agents are co-administered.⁵

The half-life of valproate in adults is 12 to 16 hours. In epileptic patients receiving polytherapy, the half-life is approximately nine hours, although five hours has also been reported. The half-lives in school-age children and young adolescents are well within the range of values in adults. Elimination half-lives are longer in neonates and generally shorter during middle and late infancy. Although hepatic clearance is reduced, the half-life in geriatric patients is approximately 15 hours. This has been attributed to the larger free fraction observed in this age group, especially in those with hypoalbuminemia.

Valproic acid – price of analysis in Dnipro in INVITRO

Study material
Blood serum

Method of determination
Fluorescent polarization.

Therapeutic drug monitoring of valproic acid is of great importance in the treatment of epilepsy along with the analysis of clinical data and electroencephalography, neuroimaging methods.

Determination of the concentration of valproic acid in the blood makes it possible to control the treatment process, to avoid possible complications associated with the side effects of anticonvulsants.

In many cases, after correction of therapy carried out under the supervision of drug monitoring, severe manifestations of the disease in patients decreased or regressed.

What is Valproic Acid

Valproic acid is a drug from the group of anticonvulsants that stop seizures. This drug is almost completely absorbed. After taking it, at least three days must pass for the valproic acid content in the blood to become relatively constant.Only under such conditions will a blood test for valproic acid show a reliable result.

Preparation before examination

The analysis for the content of valproic acid in the blood does not require special preparation. The only condition is to take blood before taking the drug and after taking it two hours later. That is, the sampling of biological material must be done twice in order to correctly understand the probable violations against the background of receiving this medication.

Interpretation of results

If the level of valproic acid exceeds the norm, then the daily dosage of the drug is revised downward.

If there is a low concentration of the drug in the body and the convulsive readiness of the brain is preserved, its dose is increased.

Thus, the analysis for valproic acid in the blood makes it possible to choose the minimum dose of the drug, which will be as harmless and effective as possible.

Indications for its appointment are various forms of epilepsy, it is also attributed to anxiety, myoclonic seizures, febrile convulsions in a child, and so on.

Valproic acid has a complex mechanism of action.It affects both mediator-independent and mediator-dependent cellular processes. The prescription for the purchase of valproic acid INN in a granule and other similar drugs is prescribed by the attending physician.

It has been established that food can contain substances that act on the human brain in the same way as drugs that stabilize mood. Chocolate, berries (blueberries, raspberries, strawberries), antioxidant teas, foods containing Omega-3 will increase energy levels and help fight stress, and they are affordable.

INVITRO Laboratory quickly cope with these studies, providing you with accurate results.

90,000 Epilepsy and other convulsive conditions

The onset of a single seizure characteristic of epilepsy is possible due to the specific reaction of a living organism to the processes that have occurred in it. According to modern concepts, epilepsy is a heterogeneous group of diseases, the clinic of chronic cases of which is characterized by recurrent convulsive seizures.The pathogenesis of this disease is based on paroxysmal discharges in the neurons of the brain. Epilepsy is characterized mainly by typical recurrent seizures of a different nature (there are also equivalents of epileptic seizures in the form of sudden mood disorders (dysphoria) or characteristic disorders of consciousness (twilight clouding of consciousness, somnambulism, trances), as well as the gradual development of personality changes characteristic of epilepsy and (or ) characteristic epileptic dementia.In some cases, epileptic psychoses are also observed, which are acute or chronic and are manifested by such affective disorders as fear, melancholy, aggressiveness or heightened ecstatic mood, as well as delusions, hallucinations. If the occurrence of epileptic seizures has a proven connection with somatic pathology, then we are talking about symptomatic epilepsy. In addition, within the framework of epilepsy, the so-called temporal lobe epilepsy is often distinguished, in which a convulsive focus is localized in the temporal lobe.Such an allocation is determined by the peculiarities of the clinical manifestations characteristic of the localization of a convulsive focus in the temporal lobe of the brain. Neurologists and epileptologists are involved in the diagnosis and treatment of epilepsy.

In some cases, seizures complicate the course of a neurological or physical illness or brain injury.

Epileptic seizures can have different manifestations depending on the etiology, localization of the lesion, EEG characteristics of the level of maturity of the nervous system at the time of the seizure development.Numerous classifications are based on these and other characteristics. However, from a practical point of view, it makes sense to distinguish between two categories:

Primary generalized seizures

Primary generalized seizures are bilateral symmetrical, without focal manifestations at the time of onset. These include two types:

• tonic-clonic seizures (grand mal)
• absences (petit mal) – short periods of loss of consciousness.

Partial seizures

Partial or focal seizures are the most common manifestation of epilepsy. They arise when nerve cells are damaged in a specific area of ​​one of the cerebral hemispheres and are subdivided into simple partial, complex partial and secondary generalized.

• simple – no impairment of consciousness occurs with such attacks
• complex – seizures with impairment or change in consciousness, caused by areas of overexcitation of various localization and often turn into generalized.
• secondary generalized seizures are characterized by onset in the form of a convulsive or non-convulsive partial seizure or absence with subsequent bilateral spread of convulsive motor activity to all muscle groups.

Epileptic seizure

The occurrence of an epileptic seizure depends on a combination of two factors of the brain itself: the activity of the convulsive focus (sometimes also called epileptic) and the general convulsive readiness of the brain.Sometimes an epileptic seizure is preceded by an aura (Greek word meaning “breath”, “breeze”). The manifestations of the aura are very diverse and depend on the location of the part of the brain whose function is impaired (that is, on the localization of the epileptic focus). Also, certain states of the body can be a provoking factor for an epileptic seizure (seizures associated with the onset of menstruation; seizures that occur only during sleep). In addition, a number of environmental factors (such as flickering light) can trigger an epileptic seizure.There are a number of classifications of characteristic epileptic seizures. From the point of view of treatment, the most convenient classification is based on the symptoms of seizures. It also helps distinguish epilepsy from other paroxysmal seizure conditions.

Diagnosis of epilepsy

Electroencephalography

For the diagnosis of epilepsy and its manifestations, the method of electroencephalography (EEG) has become widespread, that is, the interpretation of the electroencephalogram.Particularly important is the presence of focal “peak-wave” complexes or asymmetric slow waves, indicating the presence of an epileptic focus and its localization. The presence of a high convulsive readiness of the whole brain (and, accordingly, absences) is indicated by generalized peak-wave complexes. However, it should always be remembered that the EEG reflects not the presence of a diagnosis of epilepsy, but the functional state of the brain (active wakefulness, passive wakefulness, sleep and sleep phases) and can be normal even with frequent seizures.Conversely, the presence of epileptiform changes on the EEG does not always indicate epilepsy, but in some cases it is the basis for the appointment of anticonvulsant therapy even without obvious seizures (epileptiform encephalopathy).

Treatment of the disease is carried out both on an outpatient basis (by a neurologist or psychiatrist) and inpatiently ^{(in neurological hospitals and departments or in psychiatric departments – in the latter, in particular, if a patient with epilepsy has committed socially dangerous acts in a temporary mental disorder or in case of chronic mental disorders and compulsory medical measures were applied to him).In the Russian Federation, involuntary hospitalization must be sanctioned by a court. In especially difficult cases, this is possible before the judge makes a decision. Patients who are forcibly placed in a psychiatric hospital are recognized as disabled for the entire period of being in the hospital and are entitled to receive pensions and benefits in accordance with the legislation of the Russian Federation on compulsory social insurance [7] .}

Drug treatment for epilepsy

Main article: Anticonvulsants

• Anticonvulsants, another name for anticonvulsants, reduce the frequency, duration, and in some cases completely prevent seizures.

In the treatment of epilepsy, anticonvulsants are mainly used, the use of which can continue throughout a person’s life. ^{The choice of anticonvulsant depends on the type of seizures, epilepsy syndromes, health conditions and other medications the patient is taking. It is recommended to use one product at the beginning. In the event that this does not have the desired effect, it is recommended to switch to another medicine. Take two drugs at the same time only if one does not work.]
In about half of the cases, the first remedy is effective, the second has an effect in about 13% more. A third or a combination of the two can help an additional 4%. ]
In about 30% of people, seizures continue despite treatment with anticonvulsants.}

Potential drugs include phenytoin, carbamazepine, valproic acid, and are approximately equally effective for both partial and generalized seizures (absences, clonic seizures). In the UK, carbamazepine and lamotrigine are recommended as first-line drugs for partial seizures, and levetiracetam and valproic acid are second-line drugs because of their cost and side effects.Valproic acid is recommended as the first line of treatment for generalized seizures, and lamotrigine as the second; in those who do not have seizures, ethosuximide or valproic acid is recommended, which is especially effective for myoclonic and tonic or atonic seizures.

• Neurotropic drugs – can inhibit or stimulate the transmission of nervous excitement in various parts of the (central) nervous system.
• Psychoactive substances and psychotropic drugs affect the functioning of the central nervous system, leading to a change in mental state.
• Racetam is a promising subclass of psychoactive nootropic substances.

Consequences of craniocerebral trauma (concussion of the brain and its consequences, bruising of the brain, hemorrhage, hematomas), consequences of spinal trauma. ConsequencesConsequences

As already written above, you can never neglect the intervention of doctors, even with the mildest degrees of injury. In the worst cases, this leads to undesirable consequences.

For example, in acute forms of manifestation

• depression;

90,051 mood swings;

• Partial memory impairment;
• insomnia.

Such symptoms can persist even with mild injuries if the doctors do not follow the clear treatment instructions.

After the end of treatment and complete recovery, for a firm conviction in the retreat of the disease, it is necessary to undergo a control examination.

A concussion — is it as harmless as it seems? Is a concussion as harmless as it seems?

Concussion is considered a mild closed craniocerebral injury (CCI), diagnosed more often than others.Concussion itself does not pose a danger to human life and health, provided that the recommended treatment is properly treated and the recommended regimen is followed, but sometimes after an injury, undesirable consequences develop in the form of various unpleasant symptoms.

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90,000 Which drug is safer in patients with post-stroke epilepsy?

Relevance

Valproate is the first-line therapy for patients with post-stroke epilepsy.However, the results of a new study show that this drug is associated with an increased risk of death in this group of patients. The data were presented at the 73rd meeting of the American Epilepsy Society.

Mortality is high in patients with stroke, but it rises even more in patients with epilepsy after stroke.

Methods

A new study assessed the relationship between antiepileptic therapy and the risk of death from all causes and cardiovascular causes.

The researchers defined post-epileptic epilepsy as seizures that occurred more than 1 week after a stroke.

The study included 2926 patients (46% women) from Sweden with a stroke that was transmitted from 2005 to 2010. All patients were alive for more than 2 months after stroke and received long-term antiepileptic therapy.

Of all patients, 1359 patients received carbamazepine, 569 patients received valproic acid, 377 received levetiracetam, and 349 received lamotrigine.

Total mortality was considered as primary endpoint . Secondary endpoint was cardiovascular mortality.

Results

During the study period 1801 patients died.

• After adjusting for age, gender, stroke subtype, stroke severity, hypertension, atrial fibrillation, diabetes, smoking and statin use, it was shown that the death rate was significantly higher (35%) with the use of valproic acid than carbamazepine (hazard ratio , 1.35; 95% confidence interval [CI], 1.18 – 1.56).In contrast, all-cause mortality was significantly lower with lamotrigine than with carbamazepine (hazard ratio, 0.75; 95% CI, 0.62-0.91).

90,051 1131 out of 1801 patients died from cardiovascular causes. The incidence of cardiovascular death was similar to that of total death and depended on the antiepileptic drug used.

• Researchers believe that the increased relative risk of death with valproic acid may be partially explained by weight gain, which is known to be an important risk factor for cardiovascular disease.

Source : American Epilepsy Society (AES) 73rd Annual Meeting 2019: Abstract 1.221, platform session E05. December 2019.

Imipenem, Cilastatin, and Relebactam | Memorial Sloan Kettering Cancer Center

This document, provided by Lexicomp ^® , contains all the necessary information about the drug, including the indications, route of administration, side effects and when you should contact your healthcare provider.

Trade names: USA

Recarbrio

What is this drug used for?

• It is used to treat various types of bacterial infections.

What do I need to tell my doctor BEFORE taking this drug?

• If you are allergic to this drug, any of its ingredients, other drugs, foods or substances. Tell your doctor about your allergy and how it manifested itself.
• If you have kidney disease.
• If you are taking any of the following drugs: divalproex, ganciclovir, or valproic acid.

This list of drugs and diseases that may be adversely associated with this drug is not exhaustive.

Tell your doctor and pharmacist about all the medicines you take (both prescription and over-the-counter, natural products and vitamins) and your health problems. You need to make sure that this drug is safe for your medical conditions and in combination with other drugs you are already taking.Do not start or stop taking any drug or change the dosage without your doctor’s approval.

What do I need to know or do while I am taking this drug?

• Tell all healthcare providers that you are taking this drug. These are doctors, nurses, pharmacists and dentists.
• Do not use for longer than the prescribed time. A secondary infection is possible.
• In rare cases, severe and sometimes deadly allergic side effects have occurred with these drugs.
• This drug may increase the risk of seizures in some people, including people with a history of seizures. Talk with your doctor to see if you are at increased risk of seizures with this drug.
• Tell your doctor if you are pregnant, planning to become pregnant, or breastfeeding. The benefits and risks for you and your child will need to be discussed.

What side effects should I report to my doctor immediately?

WARNING. In rare cases, some people with this drug can have serious and sometimes deadly side effects. Call your doctor right away or get medical help if you have any of the following signs or symptoms, which may be associated with serious side effects:

• Signs of an allergic reaction, such as rash, hives, itching, reddened and swollen skin with blistering or scaling, possibly associated with fever, wheezing or wheezing, tightness in the chest or throat, difficulty breathing, swallowing or speaking, unusual hoarseness, swelling in the mouth, face, lips, tongue, or throat.
• Signs of low potassium, such as muscle pain or weakness, muscle cramps, or a feeling of an irregular heartbeat.
• Signs of low sodium levels such as headache, trouble concentrating, memory impairment, confused thinking, weakness, seizures, and balance problems.
• Convulsions.
• Confusion of consciousness.
• For problems with body movement control.
• Feeling extremely tired or weak.
• Diarrhea is common with antibiotics. In rare cases, severe diarrhea caused by the bacteria Clostridium difficile (C. diff.) [CDAD] can occur. This sometimes leads to gut problems that end in death. CDAD can occur during or several months after taking antibiotics. If you have pain, abdominal cramps, or very loose, watery or bloody stools, see your doctor right away. Check with your doctor before treating diarrhea.

What are some other side effects of this drug?

Any medicine can have side effects. However, many people have little or no side effects. Call your doctor or get medical help if these or any other side effects bother you or do not go away:

• Nausea.
• Diarrhea.

This list of potential side effects is not exhaustive.If you have any questions about side effects, please contact your doctor. Talk to your doctor about side effects.

You can report side effects to the National Health Office.

You can report side effects to the FDA at 1-800-332-1088. You can also report side effects at https://www.fda.gov/medwatch.

What is the best way to take this drug?

Use this drug as directed by your healthcare practitioner.Read all the information provided to you. Follow all instructions strictly.

• This drug is administered by intravenous infusion continuously over a period of time.

What should I do if a dose of a drug is missed?

• Call your doctor for further instructions.

How do I store and / or discard this drug?

• If you need to store this drug at home, ask your doctor, nurse, or pharmacist for information about how it is stored.

General information on medicinal products

• If your health does not improve or even worsens, see your doctor.
• You should not give your medicine to anyone and take other people’s medicines.
• Store all medicines in a safe place. Keep all medicines out of the reach of children and pets.
• Dispose of unused or expired drugs.Do not empty into toilet or drain unless directed to do so. If you have any questions about the disposal of your medicinal products, consult your pharmacist. Your area may have drug recycling programs.
• Some medicines may come with other patient information sheets. If you have questions about this drug, talk with your doctor, nurse, pharmacist, or other healthcare professional.
• Some medicines may come with other patient information sheets. Check with your pharmacist. If you have questions about this drug, talk with your doctor, nurse, pharmacist, or other healthcare professional.
• If you think an overdose has occurred, call a Poison Control Center immediately or seek medical attention. Be prepared to tell or show which drug you took, how much and when it happened.

Use of information by consumer and limitation of liability

This information should not be used to make decisions about taking this or any other drug. Only the attending physician has the necessary knowledge and experience to make decisions about which drugs are appropriate for a particular patient. This information does not guarantee that the drug is safe, effective, or approved for the treatment of any disease or specific patient.Here are only brief general information about this drug. It does NOT contain all available information on the possible use of the drug with instructions for use, warnings, precautions, information about interactions, side effects and risks that may be associated with this drug. This information should not be construed as a treatment guide and does not replace information provided to you by your healthcare professional. For complete information on the possible risks and benefits of taking this drug, consult your doctor.