Original ArticleElevation of pivaloylcarnitine by sivelestat sodium in two children
Section snippets
1. Introduction
Some oral antibiotics contain esterified pivalic acid (PVA) to increase their intestinal absorption rate [1]. Previous reports have demonstrated that long-term treatment with PVA-containing antibiotics can induce severe hypoglycemia or encephalopathy [2], [3]. This is because the serum carnitine level is reduced by esterification with PVA, which is excreted as pivaloylcarnitine (PVC) in the urine [4], [5].
Sivelestat sodium (sivelestat) is a specific inhibitor of neutrophil elastase, and it is
2.1. Case 1
A 14-day-old female was born with an extremely low birth weight (782 g) via a Cesarean section at 25 weeks and 1 day of gestation due to an intrauterine infection. She was treated with sivelestat for the prophylaxis of Wilson–Mikity syndrome soon after birth for 14 days because the level of immunoglobulin M in the serum was elevated at birth (36 mg/dL, reference value < 20 [8]). Newborn mass screening using tandem mass spectrometry (MS/MS) on day 7 was conducted at another agency and revealed elevated
3. Methods
AC on dried blood spots was pre-treated using an underivatized method as described previously [9], [10]. D9-isovalerylcarnitine (d9-IVC) was purchased from Cambridge Isotopes Laboratories to use as an internal standard. PVC and 2-metyhlbutyrylcarnitine (2MBC) standard solutions were provided by Dr. Hideki Nakajima (National Center for Child Health and Development, Tokyo, Japan).
Samples (10 μL) were analyzed using MS/MS (TQ Detector; Waters, Milford, MA, USA) via high performance liquid
4. Results
In Case 1, an increase of the C5-AC levels (4.49 μM) and a mild decrease in the free carnitine levels (C0 9.06 μM, cut-off: < 10) were observed following 14 days of treatment with sivelestat. These findings strongly suggested that the patient had IVA with secondary carnitine deficiency. However, IVA was considered to be unlikely because isovalerylglycine was not detected by a urinary organic acid analysis (Table 1). Moreover, no abnormal body smell, hypoglycemia, or elevation of the serum creatine
5. Discussion
This report described two cases with elevated PVC following the administration of sivelestat, which had never been reported before. Sivelestat is separated into a pharmacologically active form and PVA following administration in vivo. Although the pharmacologically active form is conjugated with glucoronate, the PVA would be bound to free carnitine to generate PVC, which is subsequently excreted in the urine. Therefore, sivelestat can cause secondary carnitine deficiency, as has previously been
Conflicts of interest
The authors have no conflicts of interest to declare.
Role of the funding source
This report was partially supported by grants from the Ministry of Education, Culture, Sports, Science and Technology (S.Y. and K.Y.) and the Ministry of Health, Labor and Welfare (S.Y.) of Japan.
Acknowledgments
The separation of PVC was performed at the Tokyo Health Service Association based on the method developed by Dr. Hideki Nakajima (National Center for Child Health and Development).
References (14)
- et al.
Carnitine deficiency induced by pivampicillin and pivmecillinam therapy
Lancet
(1989) - et al.
ONO-5046 is a potent inhibitor of neutrophil elastase in human pleural effusion after lobectomy
Eur. J. Pharmacol.
(1998) - et al.
Rapid determination of C4-acylcarnitine and C5-acylcarnitine isomers in plasma and dried blood spots by UPLC-MS/MS as a second tier test following flow-injection MS/MS acylcarnitine profile analysis
Mol. Genet. Metab.
(2010) - et al.
UPLC-MS/MS analysis of C5-acylcarnitines in dried blood spots
Clin. Chim. Acta
(2013) - et al.
Modifications in electrospray tandem mass spectrometry for a neonatal-screening pilot study in Japan
J. Chromatogr. B Biomed. Sci. Appl.
(1999) - et al.
Surprising causes of C5-carnitine false positive results in newborn screening
Mol. Genet. Metab.
(2014) - et al.
Alteration of ammonia and carnitine levels in short-term treatment with pivalic acid-containing prodrug
Tohoku J. Exp. Med.
(1995)
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Effects of the early administration of sivelestat sodium on bronchopulmonary dysplasia in infants: A retrospective cohort study
2017, Early Human DevelopmentCitation Excerpt :In this study, no adverse effects of early prophylactic treatment with sivelestat in preterm neonates were observed compared with the findings in patients who did not receive sivelestat. Yamada and colleagues reported that two patients exhibited elevated pivaloylcarnitine levels following treatment with sivelestat [33]. Sivelestat contains pivalic acid, similarly as certain antibiotics, and thus, this drug has the potential to cause secondary carnitine deficiency.
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