Simultaneous determination of bromvalerylurea and allylisopropylacetylurea in human blood and urine by gas chromatography–mass spectrometry

Kudo, Kazuhiko; Kiyoshima, Akiko; Ohtsuka, Yukio; Ikeda, Noriaki

doi:10.1016/s1570-0232(03)00219-8

Cited by 10 publications

(8 citation statements)

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“…[43][44][45] However, its unsaturated analogue, 2-isopropyl-∆ 4 -pentenoylurea, is available in Japan as an over-the-counter (OTC) hypnotic that is also used as an analgesic and antipyretic agent. 46 We have shown (Table 1) that VPU is less potent in the MES model than VPD, but it possesses a greater PI value (Table 1) and thus our results are in agreement with those of Tantisira et al 38 From the anticonvulsant profile of the urea derivatives of VPA's constitutional isomers analyzed in this study (Table 1), we can conclude that VCU (16) and DIU (17) are the most active compounds in the scMet model (ED 50 ) 14 and 16 mg/ kg, respectively), whereas (R,S)-PIU ( 18) and (S)-PIU (20) are the most potent compounds in the MES test (ED 50 ) 16 and 18 mg/kg, respectively). The anticonvulsant activity of PIU (18) was enantioselective in the MES model with (S)-PIU (20) exhibiting a higher potency and a wider PI value than (R)-PIU (19).…”

Section: Resultsmentioning

confidence: 99%

Potent Anticonvulsant Urea Derivatives of Constitutional Isomers of Valproic Acid

et al. 2007

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Valproic acid (VPA) is a major antiepileptic drug (AED); however, its use is limited by two life-threatening side effects: teratogenicity and hepatotoxicity. Several constitutional isomers of VPA and their amide and urea derivatives were synthesized and evaluated in three different anticonvulsant animal models and a mouse model for AED-induced teratogenicity. The urea derivatives of three VPA constitutional isomers propylisopropylacetylurea, diisopropylacetylurea, and 2-ethyl-3-methyl-pentanoylurea displayed a broad spectrum of anticonvulsant activity in rats with a clear superiority over their corresponding amides and acids. Enanatiomers of propylisopropylacetylurea and propylisopropylacetamide revealed enantioselective anticonvulsant activity, whereas only enantiomers of propylisopropylacetylurea displayed enantioselective teratogenicity. These potent urea derivatives caused neural tube defects, but only at doses markedly exceeding their effective dose, whereas VPA showed no separation between its anticonvulsant activity and teratogenicity. The broad spectrum of anticonvulsant activity of the urea derivatives coupled with their wide safety margin make them potential candidates to become new, potent AEDs.

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Section: Resultsmentioning

confidence: 99%

Potent Anticonvulsant Urea Derivatives of Constitutional Isomers of Valproic Acid

et al. 2007

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“…Reversed-phase (C 18 ) extraction gave better sample purification compared with liquid-liquid or Extrelut ® extraction in the analysis of human vitreous humor by GC-MS [17]. Since no studies focusing on the extraction procedure of morphine in solid tissues were found, we chose an Extrelut ® NT column based on our experience in the analyses of methomyl [18] and bromvalerylurea [19] using this column. Extrelut ® column, a well known sample preparation device that can be used in place of liquid-liquid extraction procedure, could absorb colored interfering compounds in solid tissues completely and clean extracts were obtained.…”

Section: Extraction Proceduresmentioning

confidence: 99%

Simple and sensitive determination of free and total morphine in human liver and kidney using gas chromatography–mass spectrometry

Kudo

Ishida

Nishida

et al. 2006

Journal of Chromatography B

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“…VCU (capuride, Pacinox) in its racemic form underwent clinical trials as a potential anxiolytic and hypnotic drug (Katz et al., 1970; Goldstein & Pfeiffer, 1971; Johnson et al., 1972; O’Neil, 2001). Two CNS‐active analogs of VCU, bromvalerylurea and allylisopropylacetylurea, are widely used in Japan as sedatives and hypnotics as well as for analgesic and antipyretic properties (Kudo et al., 2003). The major aim of the current study was to investigate whether either one of the individual stereoisomers of VCU, (2R,3S)‐VCU or (2S,3S)‐VCU (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of stereoselective anticonvulsant, teratogenic, and pharmacokinetic profile of valnoctylurea (capuride): A chiral stereoisomer of valproic acid urea derivative

et al. 2010

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SUMMARYPurpose: The purpose of this study was to evaluate the stereoselective anticonvulsant activity, neurotoxicity, pharmacokinetics, and teratogenic potential of two stereoisomers of valnoctylurea (VCU), a central nervous system (CNS)-active urea derivative of valnoctic acid, which is a constitutional isomer of valproic acid (VPA). Methods: VCU stereoisomers (2S,3S)-VCU and (2R,3S)-VCU were synthesized. Their anticonvulsant activity was determined and compared to VPA and racemic-VCU in rats utilizing the maximal electroshock seizure (MES) and the subcutaneous pentylenetetrazole (scMet) tests. Neurotoxicity was determined in rats using the positional sense test, muscle tone test, and gait and stance test. The induction of neural tube defects (NTDs) by VCU stereoisomers was evaluated in a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of VCU was studied in a stereoselective manner following intraperitoneal (i.p.) administration to rats. Results: (2S,3S)-VCU and (2R,3S)-VCU median effective dose ED 50 values were 29 mg/kg [95% confidence interval (CI) = 8-60 mg/kg] and 42 mg/kg (95% CI = 36-51 mg/kg) (MES) and 22 mg/kg (95% CI = 13-51 mg/kg) and 12 mg/kg (95%CI = 7-21 mg/kg) (scMet), respectively. (2S,3S)-VCU was more potent and had a wider safety margin (p < 0.05), defined as the protective index (PI = TD 50 /ED 50 ), at both the MES (PI > 17) and scMet (PI > 23) tests than racemic-VCU or (R,S)-VCU (PI = 2.8 and 9.9, respectively). VCU stereoisomers caused NTDs at doses >4 times that of their anticonvulsant ED 50 values. At a dose of 112 mg/kg, (2R,3S)-VCU was nonteratogenic and less embryotoxic than its stereoisomer (2S,3S)-VCU. No stereoselective pharmacokinetics was observed following intraperitoneal dosing of racemic-VCU to rats. VCU was mainly eliminated by metabolism with a half-life of 2 h. Conclusions: VCU anticonvulsant activity and wide PI values make it a potential candidate for development as a new, potent antiepileptic drug (AED).

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Simultaneous determination of bromvalerylurea and allylisopropylacetylurea in human blood and urine by gas chromatography–mass spectrometry

Cited by 10 publications

References 9 publications

Potent Anticonvulsant Urea Derivatives of Constitutional Isomers of Valproic Acid

Potent Anticonvulsant Urea Derivatives of Constitutional Isomers of Valproic Acid

Simple and sensitive determination of free and total morphine in human liver and kidney using gas chromatography–mass spectrometry

Evaluation of stereoselective anticonvulsant, teratogenic, and pharmacokinetic profile of valnoctylurea (capuride): A chiral stereoisomer of valproic acid urea derivative

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