Biomedical subjects
Publications and source records attributed to H L Kim.
Three sesquiterpene lactones (hymenoxon, helenalin, and tenulin) were tested for genotoxicity using six strains of Bacillus subtilis. Hymenoxon was found to produce lethal DNA damage in strains rec A8 and mc-1 while helenalin was lethal in strains mc-1 and rec E4. Tenulin did not produce lethal DNA damage in any of the strains tested.
The acute oral toxicity of hymenoxon is dose-dependent, and the clinical signs and pathologic lesions are qualitatively identical to those of animals fed whole bitterweed. There was no synergistic effect when sheep were fed hymenoxon with hymenolane.
Pretreatment of mice with the microsomal enzyme inducers, phenobarbital or polychlorinated biphenyl, or microsomal enzyme inhibitor, chloramphenicol, did not significantly alter the toxicity of hymenoxon. Pretreatment of mice with the hepatotoxin, carbon tetrachloride, provided significant protection against challenge dosages of hymenoxon. The LD50 of hymenoxon following carbon tetrachloride pretreatment was increased to 630 +/- 20.5 mg/kg as compared to the known oral LD50 of 241 +/- 10 mg/kg. These results suggest that a metabolite of hymenoxon may be responsible for the toxicity of this sesquiterpene lactone.
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The intraperitoneal LD50 of 7 sesquiterpene lactones were determined (in mg/kg): mexicanin-E (3, 3.08 +/- .10), helenalin (1, 9.86 +/- .08), hymenoxon (2, 16.24 +/- .10), psilotropin (4, 112.25 +/- .17), hymenoxon dimethyl ether (5, 141.42 +/- 0), tenulin (6, 184.65 +/- .06), and hymenolane (7, above 200). The toxicity of a sesquiterpene lactone depends on the number of alkylating centers such as cyclopentenone, alpha-methylene-gamma-lactone, or hemiacetal moieties in the molecules.
L-Cysteine was given IV at dosages of 34.5, 48.8, 69.0, 97.6, or 138.0 mg/kg of body weight to groups of sheep previously treated (10.6 minutes) intraperitoneally with an LD92 of hymenoxon (12.8 mg/kg). L-Cysteine at dosages of 69.0, 97.6, and 138.0 mg/kg significantly increased survival rate 8.4-, 10-, and 12.5-fold, respectively, over that of gymenoxon-treated sheep not given L-cysteine. L-Cysteine at dosages of 34.5 and 48.8 mg/kg failed to significantly reduce mortality. Surviving hymenoxon-treated sheep given 97.6 or 138.0 mg of L-cysteine/kg showed mild or no clinical signs of toxicosis. There was no dosage of L-cysteine that significantly changed the survival time for fatally intoxicated sheep.
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This investigation was undertaken to assess the combined effects of protein restriction and ultrasonic energy exposure during pregnancy on the maternal and fetal mouse. Pregnant female mice were fed diets containing either 18% casein (control diet) or 6% casein (restricted protein diet) during gestation. All animals were subjected to the ultrasonic exposure procedure (actual: 2.5 W/cm2 spatial peak; sham: 0 W/cm2; continuous wave for 20 sec at a frequency of 1 MHz) on day 8 of gestation. On day 18 of gestation, the animals were sacrificed. Products of conception were examined, and chemical analysis were performed on maternal liver, placenta and fetus. Our results suggest that there are possible influences of ultrasonic energy exposure to the mouse fetus and placenta, as indicated by the tendency toward decreases of fetal weight, placental weight, and DNA and RNA contents of both fetus and placenta, especially with restricted protein in the maternal diet during gestation. Protein restriction during pregnancy had an adverse influence on both the maternal organism and her products of conception. The nutritional needs for the fetus were not met at the expense of the maternal organism. Parameters of fetal cellular growth were reduced by gestational protein restriction indicating that there is competition for available nutrients between the fetus under time of stress. Results also show that the trends of fetal and placental growth are in the same general direction suggesting the possible usefulness of human placental tissue as a maker for fetal growth in subsequent population studies.
Our previous studies have shown an increase in the number of GABAergic and total neurons in the inferior colliculus (IC) of the genetically epilepsy-prone rat (GEPR-9) as compared to the non-seizing Sprague-Dawley (SD) rat. To determine whether an increase in neuron number in the IC is genetically associated with seizure behavior, seizing and non-seizing offspring of GEPR-9 and SD progenitor strains were studied as well as offspring from backcrosses made with F1 and either GEPR-9 or SD rats. In addition, the ontogeny of seizure behavior was studied in seizing rats from these same backgrounds. The development of seizure behavior in GEPR-9s was shown to be dependent on age and the number of exposures to sound stimulus up until the age of 9 weeks. The F1 and F2 generations displayed different audiogenic seizure profiles than those of the two progenitor strains. In the F1 generation, the ratio of seizing to non-seizing rats was always greater than 3:1, and the distribution of seizure scores was similar for males and females. In addition, the off-spring from backcrosses made with F1 rats (high or low seizing) and GEPR-9s displayed maximal audiogenic response scores (ARS) of 9, a characteristic of the GEPR-9s used in this study. The results of these genetic studies indicate a polygenetic inheritance of this autosomal dominant trait of audiogenic seizure susceptibility. For the quantitative study of neuronal density in the IC, neurons were counted from cresyl violet-stained preparations from seizing and non-seizing F1 and F2 rats, backcrosses from different categories and age-matched SD rats. Statistically significant increases in the number of both small (70% increase) and medium-sized (14% increase) neurons occurred in the high seizing animals (ARS = 7-9) as compared to either the non-seizing F2 or SD rats. In addition, a significant increase in the number of small neurons (77% increase) occurred in the high seizing offspring of the F1 X GEPR-9 backcross as compared to that of the non-seizing offspring of the F1 X SD backcross. The data from 25 rats generated a 0.9 coefficient of linear correlation between ARS and the number of small neurons. The results from the anatomical studies suggest that the inheritance of audiogenic seizures appears to be closely linked to the increase in cell number. Therefore, the increase in cell number in the IC may be an important determinant of seizure behavior for GEPR-9s.
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OBJECTIVE: To report a case of thrombocytopenia and a case of neutropenia, both associated with the use of diclofenac. CASE SUMMARIES: A 63-year-old woman was receiving diclofenac for osteoarthritis. During a hospital admission for pneumonia, she was found to have severe thrombocytopenia. Diclofenac therapy was stopped and the thrombocytopenia resolved. Several months later she was inadvertently treated with diclofenac by another physician and again experienced thrombocytopenia, which again resolved on discontinuation of the drug and has not recurred since. A 72-year-old man was receiving diclofenac for 9 months for osteoarthritis. He was then found to have asymptomatic neutropenia. Diclofenac therapy was stopped and the neutropenia resolved with no other intervention. He was not rechallenged. DISCUSSION: Severe thrombocytopenia and neutropenia are extremely rare adverse reactions to diclofenac. To date, there is only 1 case of each that is well documented and supported in the literature. CONCLUSIONS: Severe thrombocytopenia and neutropenia are potential serious adverse effects of the use of diclofenac. Patients who are receiving diclofenac and develop symptoms of either thrombocytopenia or neutropenia should have a complete blood count, and if this diagnosis is confirmed, the drug therapy should be stopped.