Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

Kizu, Rika; Nishimura, Kazuko; Satō, Reiko; Kosaki, Kenjiro; Tanaka, Toshiaki; Hasegawa, Tomonobu

doi:10.1159/000478696

Cited by 18 publications

(28 citation statements)

References 13 publications

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“…This is in agreement with the findings of Virgili et al, who demonstrated that diazoxide inhibits the production of nitric oxide in the murine model of multiple sclerosis [44]. Diazoxide is an agonist of ATP-gated potassium channels primarily used to treat patients with hypoglycaemia [15]. While calcium is more abundant in the extracellular fluid, potassium is highly concentrated in the cytosol.…”

Section: Resultssupporting

confidence: 92%

Ion Transport Modulators Differentially Modulate Inflammatory Responses in THP-1-Derived Macrophages

Mitini-Nkhoma

Fernando

Ishaka

et al. 2021

Journal of Immunology Research

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Ion transport modulators are most commonly used to treat various noncommunicable diseases including diabetes and hypertension. They are also known to bind to receptors on various immune cells, but the immunomodulatory properties of most ion transport modulators have not been fully elucidated. We assessed the effects of thirteen FDA-approved ion transport modulators, namely, ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, omeprazole, pantoprazole, phenytoin, verapamil, drug X, and drug Y on superoxide production, nitric oxide production, and cytokine expression by THP-1-derived macrophages that had been stimulated with ethanol-inactivated Mycobacterium bovis BCG. Ambroxol HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, pantoprazole, phenytoin, verapamil, and drug Y had an inhibitory effect on nitric oxide production, while all the test drugs had an inhibitory effect on superoxide production. Amiloride HCl, diazoxide, digoxin, furosemide, phenytoin, verapamil, drug X, and drug Y enhanced the expression of IL-1β and TNF-α. Unlike most immunomodulatory compounds currently in clinical use, most of the test drugs inhibited some inflammatory processes while promoting others. Ion pumps and ion channels could therefore serve as targets for more selective immunomodulatory agents which do not cause overt immunosuppression.

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Section: Resultssupporting

confidence: 92%

Ion Transport Modulators Differentially Modulate Inflammatory Responses in THP-1-Derived Macrophages

Mitini-Nkhoma

Fernando

Ishaka

et al. 2021

Journal of Immunology Research

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show abstract

“…This is in agreement with the findings of Virgili et al (2011), who demonstrated that diazoxide inhibits production of nitric oxide in murine model of multiple sclerosis [44]. Diazoxide is an agonist of ATP-gated potassium channels primarily used to treat patients with hypoglycaemia [15]. While calcium is more abundant in the extracellular fluid, potassium is highly concentrated in the cytosol.…”

Section: Ion Transport Modulators Alter Nitric Oxide Production In Masupporting

confidence: 91%

Ion transport modulators differentially modulate inflammatory responses in THP-1 derived macrophages

Mitini-Nkhoma

Fernando

Ishaka

et al. 2021

Preprint

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Ion transport modulators are most commonly used to treat various non-communicable diseases including diabetes and hypertension. They are also known to bind to receptors on various immune cells, but the immunomodulatory properties of most ion transport modulators have not been fully elucidated. We assessed the effects of thirteen FDA approved ion transport modulators namely ambroxol HCl, amiloride HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, omeprazole, pantoprazole, phenytoin, verapamil, drug X and drug Y on superoxide production, nitric oxide production and cytokine expression by THP-1 derived macrophages that had been stimulated with ethanol-inactivated Mycobacterium bovis BCG. Ambroxol HCl, diazoxide, digoxin, furosemide, hydrochlorothiazide, metformin, pantoprazole, phenytoin, verapamil and drug Y had an inhibitory effect on nitric oxide production, while all the test drugs had an inhibitory effect on superoxide production. Amiloride HCl, diazoxide, digoxin, furosemide, phenytoin, verapamil, drug X and drug Y enhanced the expression of IL-1β and TNF-α. Unlike most immunomodulatory compounds currently in clinical use, most of the test drugs inhibited some inflammatory processes while promoting others. Ion pumps and ion channels could therefore serve as targets for more selective immunomodulatory agents which do not cause overt immunosupression.

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“…In addition, they did not have data on the etiology of the hyperinsulinism or data on the rates among the different subtypes of hyperinsulinism. In a paper describing the pharmacokinetics of diazoxide from Kizu et al [14], a high incidence of hypertrichosis in 17 out of 19 patients was reported, but no major SAEs. In the recent analysis of the use of diazoxide in NICUs by Gray et al [18], they found that pulmonary hypertension occurred in 2% of patients treated with transient neonatal hypoglycemia and that worsening of fluid overload and worsening respiratory status occurred in 14 and 12% respectively.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…Diazoxide was first approved for use in 1976 by the United States Federal Drug Agency (FDA) and is approved for use in “leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extra pancreatic malignancy, islet cell adenoma, or adenomatosis” [13]. Kizu et al [14] reported population pharmacokinetics of diazoxide in children with hyperinsulinism. This study showed that steady state concentrations of diazoxide were comparable when given divided 2 or 3 times a day, and that steady state levels were reached by 96 hours.…”

Section: Introductionmentioning

confidence: 99%

“…This study showed that steady state concentrations of diazoxide were comparable when given divided 2 or 3 times a day, and that steady state levels were reached by 96 hours. In addition, they reported that the half-life was 6–28 h [14]. The FDA recommends doses of 8–15 mg/kg/day in newborns and infants and 3–8 mg/kg/day in children and adults [13].…”

Section: Introductionmentioning

confidence: 99%

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Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism

Thornton¹,

Truong²,

Reynolds³

et al. 2019

Horm Res Paediatr

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Introduction: Diazoxide is the first line and only Federal Drug Agency approved pharmacological agent for the treatment of hyperinsulinism. Its use has increased over the years to include patients with various genetic forms of hyperinsulinism, perinatal stress hyperinsulinism and infants of diabetic mothers with more babies than ever being exposed to this therapy. Methods: We performed a retrospective analysis of 194 patients with hyperinsulinism in our clinic and looked for those who had experienced serious adverse events (SAE) including pulmonary hypertension and neutropenia. We compared the rates of SAE in the different types of hyperinsulinism. Results: Out of 194 patients with hyperinsulinism, 165 (85.1%) were treated with diazoxide. There were 17 SAEs in 16 patients including 8 cases of pulmonary hypertension and 8 of neutropenia. These data show that overall the frequency of SAE associated with diazoxide use is 9.7%, but that those with perinatal stress hyperinsulinism have a much higher rate than those with genetic forms of hyperinsulinism (16.7 vs. 3.6%; p = 0.01). We also found diazoxide is associated with pulmonary hypertension (4.8% of patients treated). Although more patients with perinatal stress hyperinsulinism (7.6%) were affected than genetic hyperinsulinism (1.2%), the difference was not significant (p = 0.088). Conclusion: The rate of SAEs associated with (not necessarily caused by) diazoxide has been demonstrated. The rate of SAE in newborns with perinatal stress hyperinsulinism is significantly higher than that of otherwise healthy babies with genetic forms of hyperinsulinism, suggesting that caution should be used when prescribing diazoxide to this population. This information should help balance the risk benefit of treatment and provide guidance on screening for these complications in the population of treated patients.

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Population Pharmacokinetics of Diazoxide in Children with Hyperinsulinemic Hypoglycemia

Cited by 18 publications

References 13 publications

Ion Transport Modulators Differentially Modulate Inflammatory Responses in THP-1-Derived Macrophages

Ion Transport Modulators Differentially Modulate Inflammatory Responses in THP-1-Derived Macrophages

Ion transport modulators differentially modulate inflammatory responses in THP-1 derived macrophages

Rate of Serious Adverse Events Associated with Diazoxide Treatment of Patients with Hyperinsulinism

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