Role of lipid in sulfite-dependent propofol dimerization

BACKGROUND: During long-term intravenous infusions, sulfite in sulfite-containing propofol emulsions can cause the peroxidation of lipid and dimerization of propofol. This study evaluated the role of lipid in sulfite-dependent propofol dimerization by determining the effects of individual fatty acids in soybean oil emulsion and peroxidized lipids in a model system. METHODS: Individual fatty acids, stearic (18:0), oleic (18:1), linoleic (18:2), linolenic (18:3), and arachidonic (20:4), were added to sulfite-containing propofol emulsion and incubated for 90 min at 37 degrees C. Model systems containing soybean oil (100 microl), water (900 microl), propofol (10 mg/ml), and sulfite (0.25 mg/ml) composed of oils with different peroxide values were allowed to react for 60 min at room temperature. After the reactions, propofol dimer and propofol dimer quinone were analyzed by reversed-phase high-pressure liquid chromatography. RESULTS: Propofol did not dimerize when added to aqueous sulfite unless soybean oil was also included. The addition of the polyunsaturated fatty acids (linoleic, linolenic, arachidonic) to sulfite-containing propofol emulsion resulted in large increases of propofol dimerization compared with stearic or oleic acid. Using biphasic mixtures of soybean oil and aqueous sulfite, propofol dimerization increased with increasing peroxide content of the oil. In propofol emulsion, lipoxidase and ferrous iron in the absence of sulfite also caused the dimerization of propofol. CONCLUSIONS: These results show that lipid can play a significant role in sulfite-dependent propofol dimerization. The relation of dimerization to polyunsaturated fatty acid and soybean oil peroxide content suggests that sulfite reacts with unsaturated lipid or peroxide-modified lipid to facilitate propofol dimerization.     

Prevention of fumonisin-induced maternal and developmental toxicity in rats by certain plant extracts

In earlier work we have reported that garlic and cabbage extracts can protect laboratory animals from the toxic effects of different mycotoxins. Previous research demonstrated that fumonisin (FB) induced developmental effects in mice, rats and hamsters. The objectives of the present study were to utilize the pregnant rat as an in vivo model to compare the potential of garlic and cabbage seed extracts to prevent the developmental toxicity of FB and the effects of these extracts on sphingolipid metabolism in dam and foetus livers. Six treatment groups included a control group, a group fed on an FB-containing diet (150 mg kg(-1) feed) and groups treated orally with garlic or cabbage extracts (5 mg kg(-1) body wt.) with or without FB during gestation days 6-15. Evaluations of toxicity were performed on day 20. These include: maternal (mortality, body weight, feed intake and litter weight), developmental (embryonic resorption, foetal body weight, foetal soft-tissue anomalies and foetal skeletal examinations) and maternal and foetal sphingolipid metabolism. Fumonisin alone resulted in significant decreases in feed intake, body weight gain, litter weight, number of live foetuses and foetal body weight, whereas it increased significantly the number of resorbed foetuses and the number of skeletal malformations (30.4% for skull and 26.08% for sternebrae) and also increased the sphinganine/sphingosine (Sa/So) ratio in dam but not fetus livers. Garlic alone or plus FB was comparable to the control regarding all the tested parameters. On the other hand, cabbage seed extract alone or plus FB resulted in 10% maternal mortality and a decrease in maternal body weight and litter weight. It resulted in 4.65% skull malformations in foetuses but it was comparable to the control with regard to the other tested parameters. It could be concluded that both garlic and cabbage seed extracts have protective effects in pregnant rats. Moreover, garlic extract was found to have a greater protective effect than cabbage seed extract.     

Interactions of androgens,green tea catechins and the antiandrogen flutamide with the external glucose-binding site of the human erythrocyte glucose transporter GLUT1

This study investigates the effects of androgens, the antiandrogen flutamide and green tea catechins on glucose transport inhibition in human erythrocytes. These effects may relate to the antidiabetogenic effects of green tea. Testosterone, 4-androstene-3,17-dione, dehydroepiandrosterone (DHEA) and DHEA-3-acetate inhibit glucose exit from human erythrocytes with half-maximal inhibitions (Ki) of 39.2+/-8.9, 29.6+/-3.7, 48.1+/-10.2 and 4.8+/-0.98 microM, respectively. The antiandrogen flutamide competitively relieves these inhibitions and of phloretin. Dehydrotestosterone has no effect on glucose transport, indicating the differences between androgen interaction with GLUT1 and human androgen receptor (hAR). Green tea catechins also inhibit glucose exit from erythrocytes. Epicatechin 3-gallate (ECG) has a Ki ECG of 0.14+/-0.01 microM, and epigallocatechin 3-gallate (EGCG) has a Ki EGCG of 0.97+/-0.13 microM. Flutamide reverses these effects. Androgen-screening tests show that the green tea catechins do not act genomically. The high affinities of ECG and EGCG for GLUT1 indicate that this might be their physiological site of action. There are sequence homologies between GLUT1 and the ligand-binding domain (LBD) of hAR containing the amino-acid triads Arg 126, Thr 30 and Asn 288, and Arg 126, Thr 30 and Asn 29, with similar 3D topology to the polar groups binding 3-keto and 17-beta OH steroid groups in hAR LBD. These triads are appropriately sited for competitive inhibition of glucose import at the external opening of the hydrophilic pore traversing GLUT1.     

Pharmacological effects of intravenous melatonin: comparative studies with thiopental and propofol

Background. Possible utility of high-dose i.v. melatonin asan anaesthetic adjuvant has not been studied. This study comparedits effects with thiopental and propofol. Methods. Sprague Dawley rats were assigned to receive bolusor cumulative i.v. doses of melatonin, thiopental or propofol.Righting reflex, hindpaw withdrawal to a noxious stimulus, responseto tail clamping and haemodynamic effects were assessed. Results. Melatonin caused a dose-dependent increase in paw withdrawalthreshold and the percent of rats displaying loss of the rightingreflex. Melatonin was comparable to thiopental and propofolin terms of its rapid onset of hypnosis. The mean ED₅₀ valuesfor loss of righting reflex were 5.4 (SEM 1.2), 12.5 (1.1) and178 (1.1) mg kg^–1 for propofol, thiopental and melatonin,respectively. The percent of rats displaying loss of responseto tail clamping was greater with propofol than with melatonin(P<0.05). Haemodynamic changes produced by melatonin or propofolwere similar in onset and magnitude. Conclusions. I.V. melatonin can exert hypnotic effects similarto those observed with thiopental and propofol. Melatonin exhibitedsignificant antinociceptive effects but was less effective inabolishing the response to tail clamping. Br J Anaesth 2003; 90: 504–7     

Modulation of the pharmacokinetics of endogenous plasma uridine by 5-(phenylthio)acyclouridine, a uridine phosphorylase inhibitor: implications for chemotherapy

PURPOSE: The purpose of this investigation was to evaluate the ability of oral PTAU, 5-(phenylthio)acyclouridine, to increase the concentration of endogenous plasma uridine. PTAU is a new potent and specific inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3), the enzyme responsible for uridine catabolism. This compound was designed as a lipophilic inhibitor in order to facilitate its access to the liver and intestine, the main organs involved in uridine catabolism. METHODS: PTAU was administered to mice orally and parenterally. The plasma levels of PTAU as well as those of uridine and its catabolite uracil were measured by HPLC, and pharmacokinetic analysis was performed. RESULTS: PTAU was fully adsorbed after oral administration (over 100% oral bioavailability) and no PTAU metabolites were detected. PTAU administered orally had no apparent toxicity at doses up to 120 mg/kg per day for 5 days. Parenteral administration of PTAU at 30, 45 and 60 mg/kg increased the concentration of endogenous plasma uridine (1.8 +/- 0.2 microM) by approximately six-, seven-, and nine-fold, respectively. Plasma uridine concentration remained higher than control values until 8 h after PTAU administration. Similar results were obtained following oral administration of PTAU. The baseline concentrations of endogenous plasma uridine were increased by approximately six-, seven- and ten-fold by oral administration of PTAU at 30, 45 and 60 mg/kg, respectively, and remained higher than the controls until 8 h after PTAU administration. PTAU did not alter the concentration of endogenous plasma uracil. CONCLUSION: The effectiveness of the PTAU in elevating and sustaining high plasma uridine concentrations may be useful in rescuing or protecting the host from toxicities of various chemotherapeutic pyrimidine analogues as well as in the management of medical disorders that respond to the administration of uridine.     

Epidemiologic study of trichomoniasis in normal women

The prevalence of trichomonas vaginalis in a relatively unselected group of 4341 30-45 year old white women from Washington County, Maryland, was examined in Papanicolaou stained smears prepared by the self-administered irrigation smear method. 14.5% of the 4290 satisfactory smears were classified as positive for T. vaginalis. This may have been underestimated since over 1/2 of the group showed few parasites. 2.7% of the total (20% of the positive group) had heavy infestations. There was an insignificant increase between 30-34 and 40-45 year old women (13.6%-15.2%). There was a negative association between the amount of schooling and incidence of infection. Married women had 1/2 the infection incidence of widowed or never married women and one-third the incidence of divorced or separated women, a a pattern which differs from other reports. However, symptomatic unmarried women may have responded to the survey in greater numbers than symptomatic unmarried women, biasing the results. There was a significantly higher incidence of trichomoniasis among women married several times than among women married only once. There was a correlation between age at first marriage and infection incidence. The use of intravaginal contraceptive agents may have an effect on the trichomonads. There was no correlation with religion or size of household. Inverse correlations were noted between income, occupation of husband, crowding and sanitary facilities and trichomoniasis infection with an exception being the low frequency among farm women. Moderate and heavy cigarette smokers had higher infection rates than light and nonsmokers, and there was a high association of trichomoniasis with abnormal cytologic findings. These were all consistent with a venereal mode of transmission.     

Relation of various epidemiologic factors to cervical cancer as determined by a screening program

This study attempted to elucidate the etiology of cervical cancer by examining its association with a number of factors in a relatively unselected group of women. In 1963, a cytologic screening program was undertaken in Washington County, Maryland. The irrigation smear method was used. The final study group of 4341 was 46% of all white women aged 30-45 years enumerated in the census. Of the 4290 satisfactory smears, 46 were positive or suspicious. Subsequent investigation confirmed 31 cases of which 28 were at Stage 0 and 3 were invasive carcinoma of the cervix. Of 15 with suspicious cytologic findings 6 had confirmed findings, all of which were at Stage 0. Women who were never married had no confirmed cases. Currently-married women had lower rates than women whose marriages had been disrupted. Those who were married at age 16 or earlier had higher rates of cervical cancer as did those from lower socioeconomic levels. Having had multiple sex partners was associated with an increased risk of developing cervical cancer. Smokers had slightly higher rates than nonsmokers. Trichomonas vaginali s infestation was associated with higher rates. Findings indicate that trichomoniasis and cervical cancer are both associated with sexual activity.