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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Valproic acid is a broad-spectrum antiepileptic drug used in the treatment of epilepsy and commonly used in other conditions such as bipolar disorder&#44; schizophrenia and migraine&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Valproic acid intoxication is associated with remarkable morbidity and potential life-threatening complications&#46; Current management options for valproate toxicity are limited and often associated with challenges such as delayed elimination and increased half-life&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">We describe the case of a patient in which we used meropenem as an adjunct therapy in the management of valproic acid toxicity&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In April 2023&#44; a 59-year-old woman&#44; with a medical history of Schizoaffective disorder and a previous suicide attempt through intentional overdose in 2004&#44; was found by her family at home with low level of consciousness following a drug overdose&#46; The time of ingestion was unknown&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">She presented to the emergency department with a persistently low Glasgow Coma Scale of 4&#47;15&#44; miotic pupils&#44; tachycardia and difficulty of breathing&#46; The patient was administered 50&#8239;mg of activated charcoal via nasogastric tube&#44; 0&#46;4&#8239;mg of naloxone&#44; and 1&#8239;mg of flumazenil&#46; However&#44; there was a minimal response to the latter&#44; characterized by a flexor response of the limbs and the emission of guttural sounds upon painful stimulation&#46; A flumazenil 0&#46;4&#8239;mg&#47;h continuous infusion was initiated but the Glasgow Coma Scale did not improve&#44; leading to her prompt intubation for airway protection&#46; She was then transferred to the Intensive Care Unit while remaining hemodynamically stable and sedated&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The initial laboratory tests showed an increased anion gap metabolic acidosis&#44; with lactic acid concentration of 3&#46;4&#8239;mmol&#47;L&#44; pH 7&#46;33&#44; ammonia concentration of 315&#46;55&#8239;&#181;g&#8239;mol&#47;L&#44; valproic acid concentration of 503&#46;06&#8239;&#181;g&#47;mL &#40;normal range 50&#8722;100&#8239;&#181;g&#47;mL&#41; and an olanzapine concentration of 175&#8239;ng&#47;mL &#40;normal range 20&#8722;80&#8239;ng&#47;mL&#41;&#46; Benzodiazepines were also detected in the urine&#46; The patient was administered levocarnitine to prevent and reverse valproate-related metabolic disorders&#46; A 12-lead electrocardiogram revealed an initial QTc of 464&#8239;msec&#44; a chest X-ray indicated no signs of aspiration pneumonia&#46; However&#44; it was decided to begin empiric antibiotic therapy with amoxicillin&#47;clavulanic acid&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The patient&#39;s valproic acid concentrations subsequently decreased to 296&#46;85&#8239;&#181;g&#47;mL and 282&#46;06&#8239;&#181;g&#47;mL at 2 and 10&#8239;h after admission&#44; respectively&#46; We calculated the individual pharmacokinetics parameters using the Bayesian forecasting model that contains a population model &#40;14&#8211;70 years&#41; of valproic acid &#40;Abbottbase pharmacokinetic system PKS&#174;&#44; Abbott Laboratories&#44; PKS&#44; Chicago&#44; IL&#44; USA&#41;&#46; The maximum serum concentrations of valproic acid allowed in this model were 250&#46;00&#8239;&#181;g&#47;mL&#46; Accepting this adjustment&#44; the predicted valproate serum concentrations in our patient at 36&#8239;h of admission were still above the normal range &#40;118&#46;15&#8239;&#181;g&#47;mL&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">After that&#44; it was decided to prescribe a single dose of 1&#8239;g of meropenem&#46; Following meropenem administration&#44; 15&#8239;h later &#40;36&#8239;h after admission&#41;&#44; serum valproic acid concentrations declined to 13&#46;9&#8239;&#181;g&#47;mL&#44; below subtherapeutic concentrations&#46; Her ammonia concentration reached normal range and the patient showed increased alertness and started responding to commands&#46; The patient was transferred out of the Intensive Care Unit on the 3rd day of hospitalization and ultimately discharged to inpatient psychiatry&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Valproic acid exhibits a complex nonlinear pharmacokinetic profile and is highly bound to albumin&#46; The unbound fraction of valproic acid in the serum varies between 6&#37; and 10&#37;&#46; However&#44; this percentage is influenced by factors such as serum albumin concentration&#44; serum VPA concentration&#44; age&#44; and the presence of end-organ failure&#46; Therefore&#44; relying solely on the total serum concentration of valproic acid can sometimes be misleading&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The pharmacological mechanisms underlying the interaction between valproic acid and carbapenem antibiotics&#44; such as meropenem&#44; are complex and not well defined&#46; Evidence suggests that carbapenems may influence valproic acid absorption&#44; distribution&#44; and metabolism&#44; leading to a rapid and pronounced reduction in serum valproate concentrations&#44; and increasing the risk of seizures in epileptic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Because of this interaction&#44; it is generally recommended to avoid the use of these two medications concurrently&#46; However&#44; based on various cases published in the literature<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;8</span></a> we intentionally used a carbapenem to decrease valproic acid concentrations in our patient&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes all the published studies regarding intentional use of VPA-carbapenem interaction in non-epileptic patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">We used meropenem as it is the most extensively described carbapenem causing this interaction&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Nevertheless&#44; other authors have used ertapenem with successful outcomes&#46; Wu CC et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> suggest that ertapenem and meropenem have a greater effect on VPA serum concentration than imipenem&#47;cilastatin&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A 1&#8239;g dose of meropenem was sufficient in our patient&#44; and contrary to Khobrani MA et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> we did not switch the antibiotic therapy for the treatment of aspiration pneumonia in favor of meropenem&#46; The majority of the patients received a carbapenem course lasting more than 72&#8239;h&#44; making it unlikely to adversely impact on antimicrobial resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Finally&#44; it should be noted that carbapenems have been mostly used intentionally to treat valproic acid overdose in patients with low risk of seizure&#44; and no adverse events were reported in this population&#46; Cunningham&#44; D et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and Mu&#241;oz-Pichuante D&#46; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> reported this use in two epileptic patients &#40;not included in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; who showed no evidence of seizure activity&#46; Further studies are needed in order to assess the safety of carbapenems in epileptic patients in this scenario&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The administration of meropenem was safe and resulted in an important reduction in serum valproate concentrations in our patient&#44; improved clinical outcomes&#44; and avoided the need for invasive procedures such as dialysis&#46; The use of meropenem in the management of valproic acid toxicity holds promise and may provide a valuable addition to the current treatment strategies for this challenging condition&#46;</p></span>"
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Doad G et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Thomas C et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Sanivarapu R et al&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Smolders E&#46; J et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Our patient&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bipolar disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bipolar disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mood disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bipolar disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bipolar disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bipolar and Schizoaffective disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Schizoaffective disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">45&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">29&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbapenem used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ertapenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ertapenem and meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total VPA serum concentrations previous carbapenem administration &#40;&#181;g&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">415&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">278&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">145&#46;60<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">844&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">289&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Time to subtherapeutic VPA serum concentrations after the first dose of carbapenem &#40;hours&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Posology and Total number of carbapenem doses &#40;n&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">500&#8239;mg q6h &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;1&#41; &#43;2&#8239;g q8h &#40;not known&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g q8h &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g q8h &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Concomitant therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Activated charcoal &#40;AC&#41; and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3670682.png"
              ]
            ]
          ]
          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The patient experienced a peak of 224&#8239;&#181;g&#47;mL in VPA serum concentrations between ertapenem and meropenem administration&#46; Peaks can be attributed to the variable pharmacokinetics of the extended-release VPA formulation&#46;</p>"
            ]
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Scientific Letter
Meropenem for the management of valproic acid intoxication: a case report and a review of the literature
Uso de meropenem para el manejo de la intoxicación por valproico: descripción de un caso y revisión de la literatura
María Romero Carratalaa, Luis Pérez de Amezaga Tomásb,
Corresponding author
luis.perezadeamezaga@hsll.es

Corresponding author.
, María Sala Carazoa, Gemma Rialp Cerveraa
a Intensive Care Unit Deparment, Son Llàtzer Hospital, Palma de Mallorca, Spain
b Pharmacy Department, Son Llàtzer Hospital, Palma de Mallorca, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Valproic acid is a broad-spectrum antiepileptic drug used in the treatment of epilepsy and commonly used in other conditions such as bipolar disorder&#44; schizophrenia and migraine&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Valproic acid intoxication is associated with remarkable morbidity and potential life-threatening complications&#46; Current management options for valproate toxicity are limited and often associated with challenges such as delayed elimination and increased half-life&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">We describe the case of a patient in which we used meropenem as an adjunct therapy in the management of valproic acid toxicity&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In April 2023&#44; a 59-year-old woman&#44; with a medical history of Schizoaffective disorder and a previous suicide attempt through intentional overdose in 2004&#44; was found by her family at home with low level of consciousness following a drug overdose&#46; The time of ingestion was unknown&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">She presented to the emergency department with a persistently low Glasgow Coma Scale of 4&#47;15&#44; miotic pupils&#44; tachycardia and difficulty of breathing&#46; The patient was administered 50&#8239;mg of activated charcoal via nasogastric tube&#44; 0&#46;4&#8239;mg of naloxone&#44; and 1&#8239;mg of flumazenil&#46; However&#44; there was a minimal response to the latter&#44; characterized by a flexor response of the limbs and the emission of guttural sounds upon painful stimulation&#46; A flumazenil 0&#46;4&#8239;mg&#47;h continuous infusion was initiated but the Glasgow Coma Scale did not improve&#44; leading to her prompt intubation for airway protection&#46; She was then transferred to the Intensive Care Unit while remaining hemodynamically stable and sedated&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The initial laboratory tests showed an increased anion gap metabolic acidosis&#44; with lactic acid concentration of 3&#46;4&#8239;mmol&#47;L&#44; pH 7&#46;33&#44; ammonia concentration of 315&#46;55&#8239;&#181;g&#8239;mol&#47;L&#44; valproic acid concentration of 503&#46;06&#8239;&#181;g&#47;mL &#40;normal range 50&#8722;100&#8239;&#181;g&#47;mL&#41; and an olanzapine concentration of 175&#8239;ng&#47;mL &#40;normal range 20&#8722;80&#8239;ng&#47;mL&#41;&#46; Benzodiazepines were also detected in the urine&#46; The patient was administered levocarnitine to prevent and reverse valproate-related metabolic disorders&#46; A 12-lead electrocardiogram revealed an initial QTc of 464&#8239;msec&#44; a chest X-ray indicated no signs of aspiration pneumonia&#46; However&#44; it was decided to begin empiric antibiotic therapy with amoxicillin&#47;clavulanic acid&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The patient&#39;s valproic acid concentrations subsequently decreased to 296&#46;85&#8239;&#181;g&#47;mL and 282&#46;06&#8239;&#181;g&#47;mL at 2 and 10&#8239;h after admission&#44; respectively&#46; We calculated the individual pharmacokinetics parameters using the Bayesian forecasting model that contains a population model &#40;14&#8211;70 years&#41; of valproic acid &#40;Abbottbase pharmacokinetic system PKS&#174;&#44; Abbott Laboratories&#44; PKS&#44; Chicago&#44; IL&#44; USA&#41;&#46; The maximum serum concentrations of valproic acid allowed in this model were 250&#46;00&#8239;&#181;g&#47;mL&#46; Accepting this adjustment&#44; the predicted valproate serum concentrations in our patient at 36&#8239;h of admission were still above the normal range &#40;118&#46;15&#8239;&#181;g&#47;mL&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">After that&#44; it was decided to prescribe a single dose of 1&#8239;g of meropenem&#46; Following meropenem administration&#44; 15&#8239;h later &#40;36&#8239;h after admission&#41;&#44; serum valproic acid concentrations declined to 13&#46;9&#8239;&#181;g&#47;mL&#44; below subtherapeutic concentrations&#46; Her ammonia concentration reached normal range and the patient showed increased alertness and started responding to commands&#46; The patient was transferred out of the Intensive Care Unit on the 3rd day of hospitalization and ultimately discharged to inpatient psychiatry&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">Valproic acid exhibits a complex nonlinear pharmacokinetic profile and is highly bound to albumin&#46; The unbound fraction of valproic acid in the serum varies between 6&#37; and 10&#37;&#46; However&#44; this percentage is influenced by factors such as serum albumin concentration&#44; serum VPA concentration&#44; age&#44; and the presence of end-organ failure&#46; Therefore&#44; relying solely on the total serum concentration of valproic acid can sometimes be misleading&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The pharmacological mechanisms underlying the interaction between valproic acid and carbapenem antibiotics&#44; such as meropenem&#44; are complex and not well defined&#46; Evidence suggests that carbapenems may influence valproic acid absorption&#44; distribution&#44; and metabolism&#44; leading to a rapid and pronounced reduction in serum valproate concentrations&#44; and increasing the risk of seizures in epileptic patients&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Because of this interaction&#44; it is generally recommended to avoid the use of these two medications concurrently&#46; However&#44; based on various cases published in the literature<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;8</span></a> we intentionally used a carbapenem to decrease valproic acid concentrations in our patient&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes all the published studies regarding intentional use of VPA-carbapenem interaction in non-epileptic patients&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">We used meropenem as it is the most extensively described carbapenem causing this interaction&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Nevertheless&#44; other authors have used ertapenem with successful outcomes&#46; Wu CC et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> suggest that ertapenem and meropenem have a greater effect on VPA serum concentration than imipenem&#47;cilastatin&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">A 1&#8239;g dose of meropenem was sufficient in our patient&#44; and contrary to Khobrani MA et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> we did not switch the antibiotic therapy for the treatment of aspiration pneumonia in favor of meropenem&#46; The majority of the patients received a carbapenem course lasting more than 72&#8239;h&#44; making it unlikely to adversely impact on antimicrobial resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Finally&#44; it should be noted that carbapenems have been mostly used intentionally to treat valproic acid overdose in patients with low risk of seizure&#44; and no adverse events were reported in this population&#46; Cunningham&#44; D et al&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> and Mu&#241;oz-Pichuante D&#46; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> reported this use in two epileptic patients &#40;not included in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; who showed no evidence of seizure activity&#46; Further studies are needed in order to assess the safety of carbapenems in epileptic patients in this scenario&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The administration of meropenem was safe and resulted in an important reduction in serum valproate concentrations in our patient&#44; improved clinical outcomes&#44; and avoided the need for invasive procedures such as dialysis&#46; The use of meropenem in the management of valproic acid toxicity holds promise and may provide a valuable addition to the current treatment strategies for this challenging condition&#46;</p></span>"
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">42&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">male&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">female&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carbapenem used&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ertapenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ertapenem and meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">meropenem&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Total VPA serum concentrations previous carbapenem administration &#40;&#181;g&#47;mL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">415&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">278&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;450&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">145&#46;60<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">844&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">289&#46;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Time to subtherapeutic VPA serum concentrations after the first dose of carbapenem &#40;hours&#41;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Posology and Total number of carbapenem doses &#40;n&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">500&#8239;mg q6h &#40;8&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;1&#41; &#43;2&#8239;g q8h &#40;not known&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g q8h &#40;3&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g q8h &#40;6&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8239;g &#40;1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Concomitant therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Activated charcoal &#40;AC&#41; and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AC and levocarnitine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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            0 => array:3 [
              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The patient experienced a peak of 224&#8239;&#181;g&#47;mL in VPA serum concentrations between ertapenem and meropenem administration&#46; Peaks can be attributed to the variable pharmacokinetics of the extended-release VPA formulation&#46;</p>"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Therapeutic VPA concentrations are considered to be 50&#8722;100&#8239;&#181;g&#47;mL&#46;</p>"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Reported non-epileptic patients with intentional use of VPA-carbapenem interaction&#46;</p>"
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0005"
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                    0 => array:2 [
                      "titulo" => "Valproate interaction with carbapenems&#58; review and recommendations"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "O&#46; Al-Quteimat"
                            1 => "A&#46; Laila"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1177/0018578719831974"
                      "Revista" => array:7 [
                        "tituloSerie" => "Hosp Pharm&#46;"
                        "fecha" => "2020"
                        "volumen" => "55"
                        "numero" => "3"
                        "paginaInicial" => "181"
                        "paginaFinal" => "187"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32508355"
                            "web" => "Medline"
                          ]
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Drug interaction between valproic acid and carbapenems in patients with epileptic seizures"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46;R&#46; Huang"
                            1 => "C&#46;H&#46; Lin"
                            2 => "S&#46;C&#46; Hsiao"
                            3 => "N&#46;C&#46; Chen"
                            4 => "W&#46;C&#46; Tsai"
                            5 => "S&#46;D&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.kjms.2016.12.001"
                      "Revista" => array:7 [
                        "tituloSerie" => "Kaohsiung J Med Sci&#46;"
                        "fecha" => "2017"
                        "volumen" => "33"
                        "numero" => "3"
                        "paginaInicial" => "130"
                        "paginaFinal" => "136"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28254115"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
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                ]
              ]
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              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Intentional use of carbapenem antibiotics for valproic acid toxicity&#58; a case report"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;A&#46; Khobrani"
                            1 => "S&#46;W&#46; Dudley"
                            2 => "Y&#46;C&#46; Huckleberry"
                            3 => "B&#46;J&#46; Kopp"
                            4 => "A&#46;D&#46; Biggs"
                            5 => "R&#46;N&#46;E&#46; French"
                          ]
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                      ]
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jcpt.12705"
                      "Revista" => array:7 [
                        "tituloSerie" => "J Clin Pharm Ther&#46;"
                        "fecha" => "2018"
                        "volumen" => "43"
                        "numero" => "5"
                        "paginaInicial" => "723"
                        "paginaFinal" => "725"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use of meropenem to treat valproic acid overdose"
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                            0 => "D&#46; Dreucean"
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                            3 => "D&#46; Gravino"
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                      "doi" => "10.1016/j.ajem.2019.158426"
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                        "tituloSerie" => "Am J Emerg Med&#46;"
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                        "numero" => "11"
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                      "titulo" => "934&#58; utilizing the carbapenem-valproic acid drug interaction in the management of valproic acid overdose"
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ISSN: 21735727
Original language: English
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