Hypercholinesterasemia with isoenzymic alteration in a family.

Hada, Toshikazu; Yamawaki, Masaru; Moriwaki, Yuji; Tamura, Shozo; Yamamoto, Tetsuo; Amuro, Yoshiki; Nabeshima, Kazuki; Higashino, Kazuya

doi:10.1093/clinchem/31.12.1997

Cited by 12 publications

(1 citation statement)

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“…[9][10][11][12] Furthermore, in some families, genetic hypercholinesterasaemia has been reported, but elevation of plasma cholinesterase activity is not known to affect the hemodynamics of the central and peripheral nervous system. [13][14][15][16] Neitlich 13 reported that one person with high serum cholinesterase activity was more resistant to succinylcholine and a muscle relaxant than were normal subjects. In contrast, the diseases associated with low cholinesterase activity are reported in liver disease, myocardial infarction, and collagen diseases.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Safety of Z‐321, a Novel Specific Orally Active Prolyl Endopeptidase Inhibitor, in Healthy Male Volunteers

Umemura¹,

Kondo²,

Ikeda³

et al. 1999

The Journal of Clinical Pharma

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This study investigates the pharmacokinetics and safety profile of Z‐321, (4R)‐3‐(indan‐2‐ylacetyl)‐4‐(1‐pyrrolidinylcarbonyl)‐1,3‐thiazolidine, a novel specific orally active prolyl endopeptidase (PEP) inhibitor. Following a preliminary safety evaluation wherein 2 subjects received 3.75 and 15 mg doses and 2 other subjects received 7.5 and 30 mg doses, 16 subjects were assigned to two groups of 8 subjects each. In each group, 6 subjects were to receive active treatment, and 1 or 2 subjects were to receive placebo treatment. One group received 60 mg under fasted and fed conditions. A separate group of 8 subjects received 60 mg of Z‐321 or a placebo in a bid regimen for 6 days and the morning dose on day 7. The concentrations of Z‐321 and its main metabolites—R‐ and S‐sulfoxide; RR‐, SS‐, and RS‐indanol; and indanolsulfoxides in plasma and urine—were determined by the HPLC method. In the multiple‐dose study, the cholinesterase activity was gradually increased and reached above the normal range on day 8 in 3 of 6 subjects given Z‐321 and gradually returned to the normal range after completion of dosing. The elevation of plasma cholinesterase activity was considered to be an action of Z‐321, but this remains to be verified. In a single‐dose study at a dose of 30 mg, headache and vomiting were observed in 1 of 6 subjects. In the multiple‐dose study, slight skin itching and eczema in 3 and 2 of 6 subjects, respectively, and headache in 2 of 6 subjects were observed, but all symptoms were not severe. There were no other abnormal findings in objective signs and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis. The Cmax of Z‐321 at 30, 60, and 120 mg in the fasting state were 63.7 ± 23.9, 102.0 ± 43.1, and 543.3 ± 437.0 ng/ml (mean ± SD), respectively, at 0.9 hours after administration, and the t1/2 was about 1.8 hours. There were no dramatic changes in the pharmacokinetics of Z‐321 in the presence of food. In the multiple‐dose study, there was no drug accumulation trend in plasma. These results indicate that Z‐321 has acceptable pharmacodynamic and pharmacokinetics profiles for clinical use without any serious adverse events, as verified in healthy young male volunteers.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics and Safety of Z‐321, a Novel Specific Orally Active Prolyl Endopeptidase Inhibitor, in Healthy Male Volunteers

Umemura¹,

Kondo²,

Ikeda³

et al. 1999

The Journal of Clinical Pharma

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Human acetylcholinesterase and butyrylcholinesterase are encoded by two distinct genes

et al. 1991

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1. Various hybridization approaches were employed to investigate structural and chromosomal interrelationships between the human cholinesterase genes CHE and ACHE encoding the polymorphic, closely related, and coordinately regulated enzymes having butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) activities. 2. Homologous cosmid recombination with a 190-base pair 5' fragment from BuChEcDNA resulted in the isolation of four overlapping cosmid clones, apparently derived from a single gene with several introns. The Cosmid CHEDNA included a 700-base pair fragment known to be expressed at the 3' end of BuChEcDNA from nervous system tumors and which has been mapped by in situ hybridization to the unique 3q26-ter position. In contrast, cosmid CHEDNA did not hybridize with full-length AChEcDNA, proving that the complete CHE gene does not include AChE-encoding sequences either in exons or in its introns. 3. The chromosomal origin of BuChE-encoding sequences was further examined by two unrelated gene mapping approaches. Filter hybridization with DNA from human/hamster hybrid cell lines revealed BuChEcDNA-hybridizing sequences only in cell lines including human chromosome 3. However, three BuChEcDNA-homologous sequences were observed at chromosomal positions 3q21, 3q26-ter, and 16q21 by a highly stringent in situ hybridization protocol, including washes at high temperature and low salt. 4. These findings stress the selectivity of cosmid recombination and chromosome blots, raise the possibility of individual differences in BuChEcDNA-hybridizing sequences, and present an example for a family highly similar proteins encoded by distinct, nonhomologous genes.

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