Toxicity of Pantetheine.

Knott, Robert; Tsao, Daniel P.N.; McCutcheon, Rob S.; Cheldelin, Vernon H.; King, Tsoo E.

doi:10.3181/00379727-95-23212

Cited by 6 publications

(4 citation statements)

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“…Pantethine's depletion of cystine from cystinotic fibroblasts ( 13) and renal cells in culture (24) is considered secondary to its production of cysteamine (14). Pantethine has very low toxicity (25,26) compared with cysteamine (27) and might serve as a neutral systemic carrier that would target cysteamine intracellularly, avoiding toxicity and maximizing effectiveness. Since the kidney has been considered the principal site ofpantethine degradation to cysteamine (12), pantethine might be particularly appropriate for treatment of cystinotic children who often develop kidney failure by 10 yr of age.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of pantethine in cystinosis.

et al. 1985

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D-Pantethine is a conjugate of the vitamin pantothenic acid and the low-molecular-weight aminothiol cysteamine. Pantethine is an experimental hypolipemic agent and has been suggested as a source of cysteamine in the treatment of nephropathic cystinosis. We treated four cystinotic children with 70-1,000 mg/kg per d oral D-pantethine and studied its metabolism. Pantethine was rapidly hydrolyzed to pantothenic acid and cysteamine; we could not detect pantethine in plasma after oral administration. The responsible enzyme, "pantetheinase," was highly active in homogenates of small intestinal mucosa and plasma. The Michaelis constant of the rat intestinal enzyme was 4.6 MM and its pH profile showed a broad plateau between 4 and 9. Pantothenate pharmacokinetics after orally administered pantethine followed an open two-compartment model with slow vitamin elimination (t1/2 = 28 h). Peak plasma pantothenate occurred at 2.5 h and levels over 250 MM were seen at 300 times normal. Apparent total body storage of pantothenate was significant (25 mg/kg), and plasma levels were elevated threefold for months after pantethine therapy. Plasma cysteamine concentrations after pantethine were similar to those reported after equivalent doses of cysteamine. However, at best only 80% white blood cell cystine depletion occurred. We conclude that pantethine is probably less effective than cysteamine in the treatment of nephropathic cystinosis and should only be considered in cases of cysteamine intolerance. Serum cholesterol was decreased an average of 14%, which supports the potential clinical significance of pantethine as a hypolipemic agent. Rapid in vivo hydrolysis of pantethine suggests that pantothenate or cysteamine may be the effectors of its hypolipemic action.

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Section: Introductionmentioning

confidence: 99%

Metabolism of pantethine in cystinosis.

et al. 1985

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“…However, cysteamine causes side effects (Corden et al , 1981) whereas pantethine has low toxicity (Knott et al , 1957; Schwartz and Bagdon, 1964) and might act as a neutral systemic carrier that would target cysteamine into the brain, avoiding toxicity and maximizing its efficacy.…”

Section: Discussionmentioning

confidence: 99%

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

Brunetti¹,

Dusi²,

Giordano

et al. 2013

Brain

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Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2−/−) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2−/− mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.

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“…Although cysteamine is being used to treat cystinosis, it has also been found to have side effects when treating this disease [25]. In contrast a study on the toxicity of pantetheine shows that this compound has low toxicity in mice [26,27]. Therefore, treatment with pantethine or pantetheine might be a safer alternative for cysteamine, because pantethine is less toxic and still will be reduced to pantetheine (1) and then further degraded by pantetheinases to cysteamine, which is the active rescue compound for cystinosis treatment.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Synthesis and Characterization of 4-Thiobutyl-triphenylphosphonium-pantetheine, a Pantetheine Derivative

Lambrechts¹,

Srinivasan²,

Geertsema

et al. 2014

ACSJ

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Pantetheine, a low molecular weight thiol, has been found to ameliorate symptoms in various disease models but specifically in Pantothenate Kinase-Associated Neurodegeneration (PKAN). Pantetheine is usually administered in its disulfide form (i.e. pantethine) since pantethine is commercially available and is reduced to pantetheine in biological systems. The applicability and efficacy of pantethine (therefore also pantetheine) as a clinical therapeutic however is hampered since both forms can be degraded by pantetheinases present in the body. Here, we report the synthesis of a masked form of pantetheine, namely 4-thiobutyltriphenylphosphonium-pantetheine (TBTPpantetheine), following our hypothesis that this pantetheine-derivative might be more stable in the presence of pantetheinases than pantetheine itself. Higher stability would enhance transport into the cytoplasm where TBTP-pantetheine is metabolized into Short Communication

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Toxicity of Pantetheine.

Cited by 6 publications

References 0 publications

Metabolism of pantethine in cystinosis.

Metabolism of pantethine in cystinosis.

Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

Synthesis and Characterization of 4-Thiobutyl-triphenylphosphonium-pantetheine, a Pantetheine Derivative

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