Carnitine Deficiency Induced by Pivampicillin and Pivmecillinam Therapy

Holme, Elisabeth; Jacobson, Carl-Eric; Nordin, Ingalill; Greter, Joachim; Lindstedt, Sven; Kristiansson, Bengt; Jodal, Ulf

doi:10.1016/s0140-6736(89)92086-2

Cited by 157 publications

(77 citation statements)

References 16 publications

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“…This therefore suggests that the wide variability in phenotypic expression in carnitine transporter defect is most likely related to exogenous stressors that exacerbate the carnitine deficiency. These could include decreased intake due to dietary carnitine deficiency (vegetarian diets), drugs that increase the elimination of carnitine (valproic acid, pivalic acid) or inhibitors of carnitine transport (verapamil, pyrilamine, b-lactam antibiotics), and conditions such as fasting or infection, which would increase the demands on carnitine-dependent fatty acid oxidation (Holme et al 1989;Lamhonwah et al 2002;Li et al 2010;Spiekerkoetter et al 2003;Tein et al 1993;Toh et al 2010). Lack of genotype/phenotype correlation could also be influenced by polygenic factors.…”

Section: Discussionmentioning

confidence: 99%

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder caused by defective cellular carnitine transport. Patients usually present with predominant metabolic or cardiac manifestations. SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5) gene. Mutation analysis of SLC22A5 gene was carried out in eight Turkish patients from six families. Six patients presented with signs and symptoms of heart failure, cardiomyopathy, and low plasma carnitine levels, five of them with concurrent anemia. A patient with dilated cardiomyopathy had also facial dysmorphia, microcephaly, and developmental delay. Tandem MS analyses in siblings of the patients revealed two more cases with low plasma carnitine levels. SCD diagnosis was confirmed in these two cases by mutation screening. These two cases were asymptomatic but echocardiography revealed left ventricular dilatation in one of them. Carnitine treatment was started before the systemic signs and symptoms developed in these patients. Mean value of serum carnitine levels of the patients was 2.63 AE 1.92 mmol/L at the time of diagnosis. After 1 year of treatment, carnitine values increased to 16.62 AE 5.11 (p < 0.001) and all responded to carnitine supplementation clinically.

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Section: Discussionmentioning

confidence: 99%

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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“…The same pathology has been observed in the interaction between blood CAR depletion and pivalic acid contained in antibiotics used currently. 18,19 Recently, Freeman et al 25 conducted an study of the role of CAR supplementation in VPA therapy using a carefully controlled, double-blind, crossover method. They assessed the effect of CAR supplementation on patients who were receiving VPA and other antiepileptic drugs.…”

Section: Figmentioning

confidence: 99%

Valproate Therapy Does Not Deplete Carnitine Levels in Otherwise Healthy Children

et al. 1998

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ABSTRACT. Objective. To determine whether children with epilepsy undergoing valproate (VPA) antiepileptic therapy and who are otherwise healthy have a lower serum level of carnitine (CAR) and a higher plasma level of plasma ammonia than do normal children.Methodology. A total of 45 children with epilepsy, 6.3 to 21.7 years of age, who were treated solely with VPA and were free of abnormal neurologic findings or nutritional problems were randomly selected (VPA-treated group). An age-matched control group (n ‫؍‬ 45) was selected from subjects without epilepsy (control group). Total (T) and free (F) serum CAR, serum VPA concentration, and the plasma ammonia level were measured and analyzed.Results. Serum VPA concentration exhibited a weak negative correlation with both T-(r ‫؍‬ ؊0.34) and F-CAR (r ‫؍‬ ؊0.41). The T-CAR levels were 55.7 ؎ 12.4 and 57.6 ؎ 12.1 mM, and the F-CAR levels 42.7 ؎ 9.9 and 44.4 ؎ 9.9 mM in the VPA-treated and control groups, respectively. Thus, there was no significant difference in T-or F-CAR levels between the VPA-treated and control groups. Plasma ammonia levels were the same in the two groups: 26 ؎ 9.2 and 29.4 ؎ 11.8 mM in the VPA-treated and control groups, respectively. There was no significant correlation between blood ammonia and either T-(r ‫؍‬ ؉0.024) or F-CAR (r ‫؍‬ ؊0.026).Conclusion. Children on a regular diet ingest a sufficient amount of CAR that more than meets their daily CAR requirement. The level of neither T-nor F-CAR in patients with epilepsy and without severe neurologic or nutritional problems being treated with VPA appeared to be affected by VPA therapy. Because the blood CAR level depends on nutritional condition rather than on blood VPA concentration, CAR deficiency caused by VPA is not likely to occur in this population. The usefulness of supplementation of CAR for this type of patient with epilepsy, therefore, must be reevaluated carefully. Pediatrics 1998;101(5). URL: http://www. pediatrics.org/cgi/content/full/101/5/e9; carnitine, valproate, valproic acid, epilepsy, liver dysfunction, hyperammonemia, lipid metabolism, Reye's syndrome, handicap, malnutrition.

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“…Various drug interferences with carnitine transport [23][24][25] have been reported to cause secondary carnitine deficiency. Interference of various xenobiotics with OCTN2 has been characterized by Ohasi et al [26].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological manipulation of L-carnitine transport into L6 cells with stable overexpression of human OCTN2

Todesco

Bur

Brooks

et al. 2008

Cell. Mol. Life Sci.

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The high-affinity Na+-dependent carnitine transporter OCTN2 (SLC22A5) has a high renal expression and reabsorbs most filtered carnitine. To gain more insight into substrate specificity of OCTN2, we overexpressed hOCTN2 in L6 cells and characterized the structural requirements of substances acting as human OCTN2 (hOCTN2) inhibitors. A 1905-bp fragment containing the hOCTN2 complete coding sequence was introduced into the pWpiresGFP vector, and L6 cells were stably transduced using a lentiviral system. The transduced L6 cells revealed increased expression of hOCTN2 on the mRNA, protein and functional levels. Structural requirements for hOCTN2 inhibition were predicted in silico and investigated in vitro. Essential structural requirements for OCTN2 inhibition include a constantly positively charged nitrogen atom and a carboxyl, nitrile or ester group connected by a 2-4-atom linker. Our cell system is suitable for studying in vitro interactions with OCTN2, which can subsequently be investigated in vivo. by a 2 to 4 atoms linker. Our cell system is suitable for studying in vitro interactions with OCTN2, which can subsequently be investigated in vivo.

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Carnitine Deficiency Induced by Pivampicillin and Pivmecillinam Therapy

Cited by 157 publications

References 16 publications

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

Valproate Therapy Does Not Deplete Carnitine Levels in Otherwise Healthy Children

Pharmacological manipulation of L-carnitine transport into L6 cells with stable overexpression of human OCTN2

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