Effect of CYP2D6 genotypes on the metabolism of haloperidol in a Japanese psychiatric population.

We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (<10 mg/day), the subjects with two or one CYP2D6*10 allele(s) showed significantly higher plasma concentrations of RHAL (0.43+/-0.23 ng/ml/mg, 0.34+/-0.16 ng/ml/mg) than those without CYP2D6*10 allele (0.18+/-0.16 ng/ml/mg). The results of this study indicate that CYP2D6*10 allele plays significant but modest role in HAL metabolism in Japanese; nevertheless, we should not lump CYP2D6*10 allele with CYP2D6*5 allele because these two mutated alleles seem to have different impacts in the metabolism of HAL.     

Pharmacological evidence that tetraethylammonium-sensitive,iberiotoxin-insensitive K+ channels function as a negative feedback element for sympathetic neurotransmission by suppressing ω-conotoxin-GVIA-insensitive Ca2+ channels in the relaxation of rabbit facial vein

Naunyn-Schmiedeberg's Archives of Pharmacology -     

Quantitative ultrastructure of physiologically identified premotoneuron terminals in the trigeminal motor nucleus in the cat

Little is known about the ultrastructure of synaptic boutons contacting trigeminal motoneurons. To address this issue, physiologically identified premotor neurons (n = 5) in the rostrodorsomedial part of the oral nucleus (Vo.r) were labeled by intracellular injections of horseradish peroxidase (HRP) in cats. The ultrastructure of 182 serially sectioned axon terminals from the five neurons was both qualitatively and quantitatively analyzed. In addition, the effects of the glycine antagonist strychnine, GABA(A) antagonist bicuculline, NMDA antagonist 2-amino-5-phosphonovalerate (APV), and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on Vo.r-induced postsynaptic potentials in trigeminal motoneurons (n = 11) were examined to evaluate potential signaling substances of the premotor neurons. Labeled boutons made synaptic contacts with either jaw-closing or -opening motoneurons. All the boutons contained pleomorphic vesicles, and most formed a single symmetric synapse either on the somata or on primary dendrites. Morphometric analyses indicated that bouton volume, bouton surface area, apposed surface area, total active zone area, and mitochondrial volume were not different between boutons on jaw-closing and -opening motoneurons. Vesicle number and density, however, were higher for boutons on jaw-closing motoneurons. The five morphological parameters were positively correlated with bouton volume. Vesicle density was the exception, which tending to be negatively correlated. Intravenous infusion of strychnine or bicuculline suppressed Vo.r-induced inhibitory postsynaptic potentials (IPSPs) in jaw-closing motoneurons. Abolition of Vo. r-induced excitatory postsynaptic potentials in jaw-opening motoneurons with APV and CNQX unmasked IPSPs. The present results suggest that premotor neurons in the Vo.r are inhibitory and that positive correlations between the ultrastructural parameters associated with synaptic release and bouton size are applicable to the interneurons, as they are in primary afferents.     

Postoperative interstitial pneumonia: 2 cases after lobectomy

Two patients with postoperative interstitial pneumonia are reported. Preoperative diagnosis was primary lung cancer without idiopathic interstitial pneumonia (IIP). Within one week after operation acute interstitial pneumonia (AIP) occurred on the nonoperated side and developed. Steroid therapy was performed but one was dead. AIP is a fatal complication after pulmonary resection and steroid therapy may be useful in some cases of postoperative AIP.     

A case of congenital cystic adenomatoid malformation of the lung in a 4-year-old child

A case of congenital cystic adenomatoid malformation (CCAM) of the lung is reported. A 3-year-old boy was admitted for elevation of infiltrative shadow in the right lower lung field on a chest X-ray. The clinical diagnosis was emphysematous bullae with inflammation. After 6 months, he had recurrent infected bullae, and was admitted. He received chemotherapy with antibiotics prior to the operation. Right lower lobectomy was performed on February 2, 1998. The resected lung was composed of multiple cysts with thin wall measuring 10-60 mm in diameter. The histological examination of specimen revealed CCAM (Stocker type I), which is rare in this age. The patient has been well for 16 months postoperatively.     

Cutaneous necrotizing vasculitis as a manifestation of familial Mediterranean fever

Familial Mediterranean Fever (FMF) is a hereditary autoinflammatory disease, which is characterized by recurrent and paroxysmal fever, peritonitis, arthritis, myalgia, and skin rashes. Although various skin lesions such as “erysipelas‐like erythema”, urticaria, nonspecific purpura, and subcutaneous nodules have been described, cutaneous vasculitis is rare. We report a Japanese case of sporadic FMF accompanied by cutaneous arteritis at the time of febrile attacks of FMF. Gene analysis revealed M694I mutation in a single allele of the MEFV gene, and oral colchicine successfully controlled both periodic fever and subcutaneous nodules of arteritis. Cutaneous necrotizing vasculitis repeatedly emerging with febrile attacks should be included among the skin manifestations of FMF.     

Evaluation of in vivo genotoxicity induced by N‐ethyl‐N‐nitrosourea,benzo[a]pyrene,and 4‐nitroquinoline‐1‐oxide in the Pig‐a and gpt assays

The recently developed Pig‐a mutation assay is based on flow cytometric enumeration of glycosylphosphatidylinositol (GPI) anchor‐deficient red blood cells caused by a forward mutation in the Pig‐a gene. Because the assay can be conducted in nontransgenic animals and the mutations accumulate with repeat dosing, we believe that the Pig‐a assay could be integrated into repeat‐dose toxicology studies and provides an alternative to transgenic rodent (TGR) mutation assays. The capacity and characteristics of the Pig‐a assay relative to TGR mutation assays, however, are unclear. Here, using transgenic gpt delta mice, we compared the in vivo genotoxicity of single oral doses of N‐ethyl‐N‐nitrosourea (ENU, 40 mg/kg), benzo[a]pyrene (BP, 100 and 200 mg/kg), and 4‐nitroquinoline‐1‐oxide (4NQO, 50 mg/kg) in the Pig‐a (peripheral blood) and gpt (bone marrow and liver) gene mutation assays. Pig‐a assays were conducted at 2, 4, and 7 weeks after the treatment, while gpt assays were conducted on tissues collected at the 7‐week terminal sacrifice. ENU increased both Pig‐a and gpt mutant frequencies (MFs) at all sampling times, and BP increased MFs in both assays but the Pig‐a MFs peaked at 2 weeks and then decreased. Although 4NQO increased gpt MFs in the liver, only weak, nonsignificant increases (two‐ or threefold above control) were detected in the bone marrow in both the Pig‐a and the gpt assay. These findings suggest that further studies are needed to elucidate the kinetics of the Pig‐a mutation assay in order to use it as an alternative to the TGR mutation assay. Environ. Mol. Mutagen. 54:747–754, 2013. © 2013 Wiley Periodicals, Inc.     

Effects of a Hypnotic Induction and an Unpleasantness-Focused Analgesia Suggestion on Pain Catastrophizing to an Experimental Heat Stimulus: A Preliminary Study

Pain catastrophizing is associated with greater levels of pain. While many studies support the efficacy of hypnosis for pain, the effect on pain catastrophizing remains unclear. The present study evaluated the effect of hypnosis on pain catastrophizing using experimental heat stimulation. Twenty-two pain patients engaged in 3 conditions: baseline (no suggestion), hypnotic induction, and hypnotic induction plus analgesia suggestion. Participants with higher baseline pain showed a significant reduction in rumination following hypnotic induction plus analgesia suggestion and significant reductions in pain due to both the hypnotic induction alone and the hypnotic induction plus analgesia suggestion. The findings suggest that unpleasantness-focused hypnotic analgesia reduces pain via its effect on the rumination component of pain catastrophizing.