Elevated Free Fractions of Valproic Acid in a Heart Transplant Patient with Hypoalbuminemia

2000 ◽  
Vol 34 (2) ◽  
pp. 183-187 ◽  
Author(s):  
Jeffrey A Haroldson ◽  
Linda E Kramer ◽  
Denise L Wolff ◽  
Kathleen D Lake
Keyword(s):  
Valproic Acid ◽  
Adverse Effects ◽  
Serum Concentration ◽  
Transplant Patient ◽  
Total Serum ◽  
Heart Transplant Patient ◽  
Serum Concentrations ◽  
Case Summary ◽  
Related Adverse Effect ◽  
Drug Concentrations

OBJECTIVE: To report a case demonstrating the importance of monitoring unbound valproic acid (VPA) serum concentrations in a patient with hypoalbuminemia. CASE SUMMARY: A 53-year-old white woman status–post heart transplantation was admitted to the hospital for declining cardiac function, possible rejection, and increased lethargy requiring intubation. An extensive workup of the patient's profound lethargy was initiated, including an evaluation of her VPA regimen. Initially, VPA dosages were adjusted based on the total serum concentration of VPA. Hypoalbuminemia compounded with increased lethargy prompted the measurement of unbound serum concentrations of VPA. The VPA dosage was then adjusted based on the unbound rather than the total VPA serum concentration; the patient eventually improved and was discharged from the hospital. DISCUSSION: Lethargy is a concentration-related adverse effect of VPA. The nonlinear pharmacokinetic and protein saturation characteristics of VPA may result in nonproportional elevations in unbound drug, and subsequent increases in adverse effects, when dosage adjustments are based solely on measurement of total VPA serum concentrations in patients with hypoalbuminemia. CONCLUSIONS: This case report suggests that appropriate monitoring of unbound drug concentrations of VPA may prevent unrecognized concentration-related adverse effects. Awareness of the pharmacokinetic relationship and adverse effects of VPA will aid clinicians in identifying the etiology of symptoms.

scholarly journals Distribution and Antimicrobial Activity of Ciprofloxacin in Human Soft Tissues

1999 ◽  
Vol 43 (5) ◽  
pp. 1307-1309 ◽  
Author(s):  
Martin Brunner ◽  
Ursula Hollenstein ◽  
Simon Delacher ◽  
Dorothea Jäger ◽  
Rainer Schmid ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
Serum Concentration ◽  
Healthy Volunteers ◽  
Intravenous Administration ◽  
Soft Tissues ◽  
Total Serum ◽  
Drug Concentrations ◽  
Simulation Based ◽  
In Vitro Simulation

ABSTRACT Interstitial ciprofloxacin concentrations in soft tissues were measured by microdialysis following intravenous administration of 200 mg to each of eight healthy volunteers. Interstitial ciprofloxacin concentrations were significantly lower than corresponding total serum drug concentrations; the interstitium-to-serum concentration ratios ranged from 0.55 to 0.73. An in vitro simulation based on interstitial pharmacokinetics showed a substantially lower antimicrobial activity than did the simulation based on serum pharmacokinetics. Thus, ciprofloxacin concentrations at the site of effect may be subinhibitory although effective concentrations are attained in serum.

Acute Seizures Due to a Probable Interaction between Valproic Acid and Meropenem

2005 ◽  
Vol 39 (3) ◽  
pp. 533-537 ◽  
Author(s):  
Francisco Javier Coves-Orts ◽  
Joaquín Borrás-Blasco ◽  
Andrés Navarro-Ruiz ◽  
Ana Murcia-López ◽  
Francisco Palacios-Ortega
Keyword(s):  
Valproic Acid ◽  
Serum Concentration ◽  
Epileptic Seizures ◽  
Clonic Seizure ◽  
Experimental Models ◽  
Tonic Clonic Seizure ◽  
Serum Concentrations ◽  
Intensive Care Unit Treatment ◽  
Acute Seizures ◽  
Probable Interaction

OBJECTIVE: To report a probable interaction between meropenem and valproic acid that resulted in the development of epileptic seizures. CASE SUMMARY: A 21-year-old woman presented to our emergency department because of a new-onset, generalized tonic—clonic seizure and was admitted to the intensive care unit. Treatment with valproic acid 1000 mg as a continuous intravenous infusion over 24 hours was initiated. On day 6, the serum concentration of valproic acid was 52.5 μg/mL. On day 13, treatment with intravenous meropenem 1 g 3 times daily was started. On day 15, when the patient was afebrile, numerous myoclonic episodes occurred involving her arms and face; the serum concentration of valproic acid at that time was 42 μg/mL. The valproic acid dose was increased to 2880 mg. Two days later, a generalized tonic—clonic seizure occurred despite the increased dosage, and the plasma concentration of valproic acid fell to 7 μg/mL. The valproic acid dose was increased the following day to 3600 mg; however, the serum concentrations remained <10 μg/mL. On day 19, based on the results of a blood culture and the suspicion of an interaction between meropenem and valproic acid, meropenem therapy was suspended. The serum concentration of valproic acid was 52.4 μg/mL on day 27. Three days later, the patient was asymptomatic and was discharged. DISCUSSION: Coadministration of valproic acid and other drugs that are metabolized by the hepatic cytochrome P450 isoenzyme system can lead to clinically relevant interactions by induction or inhibition of enzymes in shared metabolic pathways. In view of studies in experimental models, the interaction between carbapenem antibiotics and valproic acid is at least possible. Use of the Naranjo probability scale indicated a probable relationship between acute seizures and a meropenem—valproic acid interaction in this patient. CONCLUSIONS: This case report provides strong evidence for an interaction between valproic acid and meropenem. Clinicians should be aware of this potential interaction that may be associated with a serious adverse effect as the result of the decrease of the valproic acid serum concentrations.

scholarly journals Optimal therapy of epilepsy by measuring serum concentration of antiepileptic drugs with least adverse effects

2003 ◽  
Vol 56 (9-10) ◽  
pp. 419-426 ◽  
Author(s):  
Mirjana Jovicevic ◽  
Vera Diklic-Jeremic ◽  
Ivana Divjak ◽  
Marija Zarkov ◽  
Aleksandar Jovanovic
Keyword(s):  
Valproic Acid ◽  
Adverse Effects ◽  
Serum Concentration ◽  
Antiepileptic Drugs ◽  
Drug Concentration ◽  
Drug Dosage ◽  
Optimal Therapy ◽  
Clinical Centre ◽  
Epileptic Patients ◽  
Novi Sad

The study comprised 150 epileptic patients treated at the Institute of Neurology of the Clinical Centre Novi Sad. The optimal therapy with least adverse effects and seizures was achieved in patients in whom measurement of serum concentration of antiepileptic drugs was performed. Patients were divided into five groups with respect to the therapy they received: I - carbamazepine; II - valproic acid; III - polytherapy with phenobarbitone and diphenylhydantoin; IV - phenobarbitone and valproic acid; and V - phenobarbitone, valproic acid and carbamazepine. No adverse effects were recorded in over 60% of patients on monotherapy, 35% of patients who received two anticonvulsants, and 30% of patients who received three anticonvulsants. Significant correlation between drug dosage and blood drug concentration (r>0.5) was found in polytherapy with phenobarbitone, carbamazepine and valproic acid (r=0,66); and phenobarbitone and diphenylhydantoin (r=0,53).

scholarly journals Valproic Acid Concentrations in Mothers, Colostrum and Breastfed Infants during the Early Postpartum Period: Comparison with Concentrations Determined during Delivery and in the Mature Milk Period

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2074
Author(s):  
Ivana Kacirova ◽  
Milan Grundmann ◽  
Hana Brozmanova
Keyword(s):  
Valproic Acid ◽  
Serum Concentration ◽  
Lower Limit ◽  
Concentration Ratio ◽  
Maternal Serum ◽  
Serum Concentrations ◽  
Limit Of Quantification ◽  
Mature Milk ◽  
Breastfed Infants ◽  
Routine Monitoring

To obtain information on the transport of valproic acid from mothers to colostrum and breastfed infants, in this cohort study, valproic acid concentrations in maternal serum (90 subjects), colostrum and the serum of breastfed infants were analyzed in years 1993–2018, between the 2nd and 5th postnatal days. Valproic acid concentrations ranged from 4.3 to 66.5 mg/L (mean 31.2 ± 13.6 mg/L) in maternal serum, from 0.5 to 5.9 mg/L (mean 1.1 ± 1.2 mg/L) in milk, and from 0.5 to 42.9 mg/L (mean 15.4 ± 9.4 mg/L) in infant serum. The milk/maternal serum concentration ratio ranged from 0.01 to 0.22 (mean 0.04 ± 0.04), and the infant/maternal serum concentration ratio ranged from 0.01 to 1.61 (mean 0.51 ± 0.28). A significant correlation was found between serum concentrations of breastfed infants and milk concentrations, maternal serum concentrations, maternal daily dose, and dose related to maternal body weight. Valproic acid concentrations in milk and infant serum did not reach the lower limit of the reference range used for the general epileptic population, and three-quarters of the concentrations in milk were lower than the lower limit of quantification. Routine monitoring of serum concentrations of breastfed infants is not necessary. If signs of potential adverse reactions are noted, serum concentrations of the infants should be measured.

Sirolimus and mirabegron interaction in a hematopoietic cell transplant patient

2017 ◽  
Vol 24 (8) ◽  
pp. 627-631 ◽  
Author(s):  
Jeff A Engle ◽  
Christina Fair
Keyword(s):  
Serum Concentration ◽  
Transplant Patient ◽  
Organic Anion ◽  
Hematopoietic Cell ◽  
Intestinal Lumen ◽  
Cell Transplant ◽  
Weekly Dose ◽  
Serum Concentrations ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant

Purpose Hematopoietic cell transplant patients are exposed to numerous classes of medications. Transplant practitioners must vigilantly monitor for drug interactions especially involving immunosuppressants. We report a hematopoietic cell transplant patient receiving sirolimus who developed supratherapeutic serum concentrations after initiating mirabegron. Summary A 31-year-old, 98 kg female received a second umbilical cord blood transplant four years after the first transplant for relapsed acute myeloid leukemia. Mycophenolate mofetil and sirolimus were utilized for graft versus host disease prophylaxis. The patient was receiving sirolimus 2 mg daily and the serum concentration on day 26 post-transplant (day + 26) was within therapeutic range (6.7 μg/L, goal range 3–12 μg/L). Her post-transplant course was complicated by BK viruria-associated cystitis for which she was started on mirabegron. Six days after starting the new medication (day + 33), the sirolimus serum concentration increased to 19.2 μg/L. Thus mirabegron was discontinued and sirolimus was held. Sirolimus was restarted once the serum concentration was within goal and subsequently stabilized with a combination of 1 mg and 2 mg daily for a total weekly dose of 10 mg. The proposed mechanisms of interaction include: (1) sirolimus inhibition of organic anion transporting polypeptide leading to increased mirabegron in the intestinal lumen; (2) mirabegron inhibition of P-glycoprotein leading to increased absorption of sirolimus and; (3) increased sirolimus absorption leading to increased sirolimus serum concentrations. Conclusion To our knowledge, this is the first report of a potential drug interaction between sirolimus and mirabegron. Transplant specialists should be aware of this potential interaction when considering the concurrent use of these medications.

Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects

Pharmacology ◽  
2018 ◽  
Vol 102 (3-4) ◽  
pp. 133-137 ◽  
Author(s):  
Ali Sigaroudi ◽  
Martina Kinzig ◽  
Oliver Wahl ◽  
Christoph Stelzer ◽  
Michael Schroeter ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Adverse Effects ◽  
Total Serum ◽  
Serum Concentrations ◽  
Neurological Patients ◽  
Liquid Chromatography Tandem Mass ◽  
The Central Nervous System ◽  
Paired Serum

Background: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. Methods: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5–25 mg) or ramipril (n = 9, 2.5–10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. Results: CSF reached 4.1% (interquartile ranges 2.5–5%) of total serum concentrations for HCT and 2.3% (1.7–5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. Conclusion: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.

Evaluation of Transdermal Administration of Phenobarbital in Healthy Cats

2019 ◽  
Vol 55 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Daniel P. Krull ◽  
Stephanie Ann Thomovsky ◽  
Annie Vivian Chen ◽  
Katrina L. Mealey ◽  
Mark G. Papich
Keyword(s):  
Adverse Effects ◽  
Serum Concentration ◽  
Peak Concentration ◽  
Therapeutic Drug ◽  
Serum Concentrations ◽  
Short Term ◽  
Transdermal Administration ◽  
Time To Peak ◽  
Transdermal Application ◽  
Median Serum

ABSTRACT The purpose was to determine the safety and achievable serum concentrations of transdermally administered phenobarbital in healthy cats. The hypothesis was that transdermal phenobarbital would achieve therapeutic serum concentrations (15–45 µg/mL) with minimal short-term adverse effects. Enrolled cats had normal physical and neurologic exams and unremarkable bloodwork. Transdermal phenobarbital in a pluronic lecithin organogel–based vehicle was administered at a dosage of 3.0–3.1 mg/kg per ear pinna (total of 6.0–6.2 mg/kg) every 12 hr for 14 days. Serum phenobarbital concentrations were measured 3–6 hr after dosing at seven different times over 15 days. The mean and median serum concentration of phenobarbital at study completion were 5.57 and 4.08 µg/mL, respectively. Mean peak concentration and mean time to peak concentration were 5.94 µg/mL and 13.3 days, respectively. Mild adverse effects were observed. Potency was analyzed in three replicates of the transdermal phenobarbital gel administered; potencies ranged from 62.98 to 82.02%. Transdermal application of phenobarbital in healthy cats achieves a detectable, but subtherapeutic, serum concentration and appears safe in the short term. The use of therapeutic drug monitoring is recommended when this formulation of phenobarbital is used to ensure therapeutic serum concentrations are achieved.

Suppression of nanoparticle cytotoxicity approaching in vivo serum concentrations: limitations of in vitro testing for nanosafety

Nanoscale ◽  
2014 ◽  
Vol 6 (23) ◽  
pp. 14180-14184 ◽  
Author(s):  
Jong Ah Kim ◽  
Anna Salvati ◽  
Christoffer Åberg ◽  
Kenneth A. Dawson
Keyword(s):  
Cell Death ◽  
Adverse Effects ◽  
Serum Concentration ◽  
In Vitro Testing ◽  
Serum Concentrations

The adverse effects of cell death-inducing nanoparticles can be suppressed by increasing the serum concentration from typical in vitro to more realistic in vivo concentrations.

scholarly journals Valproate serum concentrations in patients with hypoalbuminemia and medical complications

2017 ◽  
Vol 7 (1) ◽  
pp. 13-15
Author(s):  
Amy VandenBerg ◽  
Jessica Broadway ◽  
Callie Lalich ◽  
Rachel Kennedy ◽  
Kristen Williams
Keyword(s):  
Valproic Acid ◽  
Serum Concentration ◽  
Free Fraction ◽  
Serum Concentrations ◽  
Model Free ◽  
Acid Protein ◽  
Patients Experience ◽  
Patients With Epilepsy ◽  
Key Terms ◽  
Free Serum

Abstract Introduction: Valproic acid (VPA) and its derivatives are highly protein bound with free fraction increasing with dose and serum concentration. Consensus guidelines regarding dose adjustment for hypoalbuminemia are not available. Methods: A literature search was performed using PubMed to identify articles with the following key terms: “valproate,” “valproic acid,” “protein binding,” “albumin,” and “hypoalbuminemia.” We report our findings as well as 5 cases involving pharmacokinetic impact of hypoalbuminemia on valproate. Results: A previously published model for normalizing VPA serum concentration for hypoalbuminemia in patients with epilepsy was compared to results for 5 cases (4 female, 1 male) in which VPA was used for psychiatric illness. Only 1 of the cases had free serum concentrations in the range that would be expected with the model. Free concentrations ranged from 22% to 83% with no clear relationship to other factors (weight, age, serum creatinine, or dose). Female patients with similar albumin had higher free fractions than the 1 male patient. Discussion: Due to the variability in pharmacokinetic impact of hypoalbuminemia, it is important to monitor patients closely for signs of VPA toxicity in cases involving altered albumin levels. It would be prudent to use free serum VPA concentrations when patients experience fluctuations in albumin or have unexpected response to medication.

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