TL;DR: DPH teratogenesis is postulated to result from DPH-epoxide formation and covalent binding of epoxide, the ultimate teratogen, to constituents of gestational tissue, which is comparable to that found in clinical therapeutics.
Abstract: The possibility that phenytoin (DPH) teratogenesis is due to an arene oxide (epoxide) metabolite was examined. On gestational day 11, Swiss mice were given teratogenic doses of DPH (50, 75 and 100 mg/kg) with and without a nonteratogenic dose of 1,2-epoxy-3,3,3-trichloropropane (TCPO; 100 mg/kg), an epoxide hydratase inhibitor. TCPO significantly increased the incidence of DPH-induced cleft lip and palate and enhanced the embryolethality 2-fold over DPH alone. Four hours after treatment with 14C-DPH (75 mg/kg, 80-90 muCi) the covalent binding of DPH radioactivity in fetuses and placentae was enhanced 2-fold in groups cotreated with TCPO (100 mg/kg). Enhancement was still evident in placentae 24 hours after treatment. There was no effect of TCPO on maternal plasma DPH level, which was comparable to that found in clinical therapeutics (20-30 microgram/ml). Likewise, fetal and placental DPH uptake was not increased by TCPO. DPH teratogenesis is postulated to result from DPH-epoxide formation and covalent binding of epoxide, the ultimate teratogen, to constituents of gestational tissue.
TL;DR: The thickened skin of patients with SS is hypoxic and TCPO2 measurements may be helpful in objectively assessing the degree of skin thickness, and the hypoxia demonstrated in SS skin may play a role in the modulation of dermal fibroblast proliferation and synthetic activity.
Abstract: • Measurement of transcutaneous oxygen pressure (Tcpo 2 ) is an established and noninvasive way of assessing cutaneous hypoxia. Since the degree of oxygenation modulates fibroblast growth and synthesis, we investigated the presence of cutaneous hypoxia in patients with systemic sclerosis (SS). We measured Tcpo 2 of the involved skin of the dorsal aspect of the forearm in 33 patients with SS and 16 control individuals (normal subjects and patients with Raynaud's disease). The degree of forearm skin thickness was assessed clinically as mild, moderate, or severe. The Tcpo 2 measurements were obtained at a sensor temperature of 44°C, which causes maximal vasodilation and eliminates the variables associated with vascular tone. Measurements were recorded while patients were breathing room air or 31% oxygen delivered by a Ventimask system (Baxter Healthcare, Ocala, Fla). We also measured the Tcpo 2 of the medial aspect of the arm when this site was uninvolved. We found that sclerodermatous skin is hypoxic when compared with the uninvolved skin of patients with SS or control individuals. The Tcpo 2 values were indirectly related to skin thickness; thus, patients whose skin was severely thickened had the lowest Tcpo 2 values. There was no correlation of Tcpo 2 values with pulmonary function tests or arterial oxygen pressure. The Tcpo 2 levels of patients with Raynaud's disease did not differ from other control individuals. The administration of oxygen increased Tcpo 2 readings in patients with SS to normal values. We conclude that the thickened skin of patients with SS is hypoxic and suggest that Tcpo 2 measurements may be helpful in objectively assessing the degree of skin thickness. The hypoxia demonstrated in SS skin may play a role in the modulation of dermal fibroblast proliferation and synthetic activity. ( Arch Dermatol 1988;128:1379-1382)
TL;DR: It is proposed that there is a familial, constitutional susceptibility factor that predisposes persons to halothane hepatitis and lymphocytes exposed to this system exhibited an increase in cytotoxicity at 0.06 mM phenytoin that was eight times greater than the increase in healthy controls.
Abstract: We studied susceptibility to halothane hepatitis with an in vitro test that detects cell damage from electrophilic drug intermediates. Metabolites of phenytoin were generated by incubation of phenytoin with rat hepatic microsomes in the presence of the epoxide hydrolase inhibitor 1,1,1-trichloropropene oxide (TCPO), which prevents the further metabolism of phenytoin to an inert metabolite. In lymphocytes exposed to this system, cytotoxicity was measured by trypan blue dye exclusion and was expressed as the percentage increase in trypan blue-positive cells after the addition of TCPO. In the presence of TCPO, lymphocytes from 11 patients with halothane hepatitis exhibited an increase in cytotoxicity at 0.06 mM phenytoin that was eight times greater than the increase in healthy controls (54 +/- 10 per cent [mean +/- S.E.M.] vs. 7.1 +/- 2.2 per cent, P less than 0.0001). Patients with other liver diseases and persons recently exposed to halothane without adverse effects did not differ from healthy controls. In three patients with halothane hepatitis who were studied serially, the lymphocyte abnormality was still present after 13 months. Family studies revealed abnormal results on 10 cytotoxicity tests among 19 members of four families. We propose that there is a familial, constitutional susceptibility factor that predisposes persons to halothane hepatitis.
TL;DR: In this paper, a peroxyoxalate chemiluminescence (CL) assay of hydrogen peroxide (H2O2) or glucose was developed by using 2, 4, 6, 8-tetrathiomorpholinopyrimido[5, 4-d]pyrimidine as a fluorescent component and bis(2, 4 6-trichlorophenyl)oxalates (TCPO) as an oxalate.
Abstract: Peroxyoxalate chemiluminescence (CL) assay of hydrogen peroxide (H2O2) or glucose was developed by using 2, 4, 6, 8-tetrathiomorpholinopyrimido[5, 4-d]pyrimidine as a fluorescent component and bis(2, 4, 6-trichlorophenyl)oxalate (TCPO) as an oxalate. Linear relationships between CL intensity and final concentration of H2O2 from 10-8 to 10-4M were obtained. The detection limit at the ratio of CL intensities for sample and blank (S/B) of 3 was 10nM. The precision for five replicate measurements at 10-5 and 10-6M of H2O2 were 17.6 and 15.7% of relative standard deviations, respectively. α-D-Glucose was transformed to β-D-glucose with mutarotase and converted to H2O2 and D-gluconic acid with glucose oxidase, which was detected by using peroxyoxalate CL reaction. A linear calibration graph was obtained up to 1.5×10-4M of glucose solution. The method was applied to the assay of glucose in human serum. The recovery was 98.2% (n=4). The method correlated well with the conventional colorimetric method (r=0.968).