Effects of Coumarin Following Perinatal and Chronic Exposure in Sprague-Dawley Rats and CD-1 Mice

Coumarin, a naturally occurring substance most frequently usedas a fragrance enhancer and stabilizer, was administered inthe diet of Sprague-Dawley rats at dose levels of 0, 333, 1000,2000, 3000, and 5000 ppm or in the diet of CD-1 mice at doselevels of 0, 300, 1000, or 3000 ppm. Rats receiving 333, 1000,and 2000 ppm coumarin were exposed to these dose levels in uteroand during the lactational period, then chronically followingweaning. Rats in the 3000- and 5000-ppm dose groups and allmice received only postweanlng chronic exposure. All male ratswere terminated after 104 weeks of postweaning exposure; femalerats were terminated after 110 weeks. Male mice were terminatedat Week 101 and female mice at Week 109. Among rats, survivalwas decreased at 333 ppm, but signilicantly increased amongrats in the 3000- and 5000-ppm dose groups. Dramatic dose-relateddecreases in body weight gain were recorded for rats receiving2000, 3000, and 5000 ppm, clearly indicating that the MTD (maximumtolerated dose, as indicated by a body weight decrement of greaterthan 10–15%) was exceeded. Food consumption also was decreasedat the three highest dose levels, although body weight decrementwas disproportionately large compared to changes in food consumption.Treatment-related decreases in hemoglobin were recorded fromWeek 6 onward. Minimal treatment-related changes in he matologyand clinical chemistry were recorded. Increased liver weightswere observed for male and female rats receiving 3000 or 5000ppm and for females only at 1000 and 2000 ppm. Increased incidencesof cholanglofibroma, cholangiocarcinoma, and parenchymal livercell tumors were observed among male and female rats receiving5000 ppm. One male rat receiving 3000 ppm devel oped a cholangiocarcinoma;no tumor increase was observed in males or females at 2000 ppmor below. Coumarin, at a dose clearly exceeding the MTD can,therefore, induce liver tumors in rats, although survival, relativeto controls, was increased at the same dose levels. Among mice,a decrease in body weight gain was reported for males in the1000- and 3000-ppm dose groups during the first 52 weeks ofthe study. No dose-related abnormalities in clinical signs,clinical pathology, hematology, or gross or microscopic pathologywere noted.     

The effect of taprostene in patients with acute myocardial infarction treated with thrombolytic therapy: results of the STARTstudy

Taprostene is a prostacyclin analogue that inhibits plateletaggregation and thus might be a useful adjuvant to thrombolyticagents in acute myocardial infarction. In a placebo-controlled dose rising study, taprostene or placebowas intravenously infused in 80 patients treated with the thrombolyticagent saruplase (rscu-PA) for acute myocardial infarction. Threedoses of taprostene were used: 6.25; 12.5; or 25.0 ng.kg^–1.min^–1.Taprostene or placebo was infused for 48 h, followed by a 24h tapering period. All 80 patients had short symptom-to-treatmentdelay and marked ST segment elevation. Patency at 90 min was documented in 58/78 patients (two patientshad no angiography). Success rate varied from 67–82% inthe four treatment arms (P=0.33). Patency after rescue PTCAwas seen in 10 out of 13 patients. Of the 58 patients havinga patent artery at 90 min, none of the 43 taprostene patientsand one of the 15 placebo patients had a reoccluded artery atthe second angiography at 32–48 h (5/58 patients had norecatheterization). Conversely, of nine patients who had successfulrescue PTCA, three of four placebo patients had a re-occludedartery at the second angiography compared to one of five taprostenepatients (one placebo patient had no recatheterization) (P=0.33). Safety evaluation revealed no major difference betweenthe placebo plus saruplase and the taprostene plus saruplasegroups. Taprostene was well tolerated up to 25 ng.kg^–1 .min^–1.Although taprostene did not affect 90 min patency, there wasa trend to better maintenance of patency after rescue PTCA.     

Malignant Ventricular Tachycardia During Propafenone Treatment in a Child with Junctional Automatic Tachycardia: Effectiveness of Intravenous Molar Sodium Lactate

Propafenone may aggravate the preexisting arrhythmia or induce another one. Usually, such proarrhythmic effects occur in patients with spontaneous ventricular arrhythmias and/or coronary heart disease with poor left ventricular function. We report the case of a 5-year-old girl with Junctional automatic tachycardia and no structural heart disease, in whom malignant ventricular tachycardia occurring during propafenone treatment could be terminated by molar sodium lactate (MSL) infusion. The serum propafenone level obtained before MSL infusion was within the therapeutic range. Two hypothesis could explain the beneficial effects of MSL in our patient: (1) alkalinization facilitates the cell membrane hyperpolarization and thus can decrease the voltage-dependent effect of Class Ic drugs, (2) alkalinization could displace propafenone from its tissue receptor sites by an increase in the nonionized fraction.     

Systemic interleukin-1 α and interleukin-2 secretion in response to acute stress and to corticotropin-releasing hormone in humans*

Abstract Acute stress results in activation of the hypothalamic-pituitary-adrenal (HPA) axis. ACTH and cortisol secretion is stimulated by corticotropin-releasing hormone (CRH). It has also been shown that activation of the HPA axis during stress is accompanied by changes in the immune response. However, little is known about the influence of acute stress on the release of cytokines such as inteleukin-1 (IL-1) or interleukin-2 (IL-2). In this study, we determined serum IL-1 α and IL-2 levels in 19 patients undergoing the acute stress of angioplasty for coronary artery disease. A second protocol was devised to determine serum IL-1 α and IL-2 concentrations as well as lymphocyte subpopulations in 10 normal volunteers receiving 1 μ kg^-1 human CRH intravenously. Finally, IL-1 α concentrations were measured in CRH-incubated mononuclear cell (MNC) and monocyte cultures. In response to the stress of angioplasty, ACTH and cortisol as well as IL-1 α and IL-2 concentrations were clearly above baseline levels (IL-1 α, mean ± SEM, baseline: 1·39 ± 0·34 ng ml^-1, after angioplasty: 2·64 ± 0·73 ng ml^-1, P < 0·05; IL-2, baseline: 1·2 ± 0·13 ng ml^-1, after angioplasty: 2·8 ± 1·14 ng ml, P < 0·05). A similar pattern was obtained in normal subjects in response to CRH (IL-1 α, baseline: 0·8 ± 0·2 ng ml^-1, after angioplasty: 3·7 ± 1·4 ng ml^-1, P < 0·05; IL-2, baseline: 1·9 ± 0·4 ng ml^-1, after angioplasty: 5·4 ± 2·2 ng ml^-1, P < 0·02). The percentage of IL-2 receptor-positive lymphocytes rose from 3·9 ± 1·2% to 6·2 ± 1·6% (P < 0·05), the relative number of CD-3 lymphocytes rose from 74·5 ± 1·6% to 78·3 ± 2·0% (P < 0·05). No significant changes were observed in the number of CD-4, CD-8, natural killer and B cells. In vitro, IL-1 α concentrations in cultures containing CRH were not significantly different from control cultures. Our data demonstrate significant activation of the HPA axis and secretion of IL-1 α and IL-2 in response to both angioplasty and CRH. Furthermore, CRH administration resulted in activation of the cellular immune system (indicated by an increase in IL-2 receptor positive lymphocytes). Our in vitro data suggest that CRH may not directly act on blood mononuclear cells to induce IL-1 α release or, alternatively, sources other than blood mononuclear cells may account for the elevated IL-1 α levels observed in vivo. We conclude that CRH may play a major role in neuroendocrine-immune interactions during acute stress.     

Local structural differences between α and β-elicitins shown by circular dichroism and ultraviolet difference spectroscopy

In order to investigate differences in the conformation of elicitins exhibiting different levels of activity (toxicity to tobacco plants). the environment of the tyrosyl residues in four elicitins has been compared by different spectroscopic methods (difference absorption and circular dichroism). We compared two α-elicitins (capsicein and parasiticein) and two β-elicitins (β-cryptogein and β-cinnamomin), that are 50–100 times more toxic than the α-ones. Thermal difference UV spectroscopy and titration experiments clearly showed the exposure of Tyr-85 by comparison of parasiticein lacking Tyr-85 and the accessibility of its hydroxyl group to the solvent. The adjacent Ty-87 was also suggested to be located at the surface. In β-cryptogein, β-cinnamoniin and capsicein the pK was measured at between 10.5 and 10.8, while in parasiticein it is higher (11.5) owing to a difference in the local environment. Thermal difference UV spectroscopy showed one more exposed tyrosine in β-elicitins than in α-ones. This difference was attributed to Tyr-12, considering the more hydrophilic characteristic of the sequence around residue 13 in β-elicitins and the role of this region in the toxicity. However, no difference in titration behaviour was noted among elicitins concerning Tyr-12. The other two tyrosines also presented an abnormal pK of titration (> 12). In all elicitins Tyr-47 was probably exposed, while Tyr-33 was probably buried and not titrated, except in β-cinnamomin at very alkaline pH.     

Endocrine factors in pre- and postmenopausal women with hidradenitis suppurativa

The relationship between hidradenitis suppurativa (HS) and hyperandrogenism is largely based on the finding of an increased free androgen index due to a low sex hormone binding globulin (SHBG). As SHBG is now believed to be regulated by factors that influence body weight, and previous studies were not controlled for body weight, we have re-evaluated the androgen status of female patients with HS. We have studied the endocrine status of 66 women with HS. Twenty-three had acne, and 23 were significantly obese (body mass index: BMI >30). There was no relationship between obesity and disease duration. Nineteen of 56 women were hirsute. A premenstrual flare in disease activity was reported by 32 women, but this was not related to menstrual disturbances. No consistent relationship was reported with pregnancy. Eight women with HS were menopausal at presentation, and one developed her disease 6 years after the menopause. Plasma androgens in women with HS were compared with controls matched for BMI and hirsuties. There was no difference between HS and controls. Testosterone and dehydroepiandrosterone sulphate were normal in all subjects with HS. In obese subjects, SHBG was reduced, consistent with BMI-matched controls. We have found no supporting evidence for biochemical hyperandrogenism in women with HS when compared with age-, weight- and hirsuties-matched controls. We report the continuation and primary development of HS in postmenopausal women.