Efficacy of sumatriptan nasal spray in recurrent migrainous headache: an open prospective study.

OBJECTIVE: To evaluate the effectiveness of sumatriptan 20 mg via nasal spray and 100-mg tablets in treating migrainous headache in patients without a concomitant migraine diagnosis. METHODS: We prospectively investigated the efficacy of sumatriptan 20 mg via nasal spray and 100-mg tablets in patients with a history of at least 5 moderate to severe headache attacks lasting 2 to 72 hours that consistently did not meet the International Headache Society (IHS) criteria for migraine or episodic tension-type headache. RESULTS: Nineteen headache attacks classifiable as migrainous disorder without aura (IHS 1.7) were evaluated in 13 patients using 20-mg sumatriptan nasal spray within a 10-week period. A 2-point decrease in headache severity on a four-point scale was achieved in 74% (95% confidence interval [CI], 50% to 89%) of the attacks within 2 hours. The pain-free incidence (a reduction in headache severity from moderate or severe to none) was 37% (95% CI, 17% to 63%) after 2 hours. Ten patients completed the second part of the study, taking oral sumatriptan for 14 migrainous attacks: a 2-point decrease in headache severity was achieved in 38% (95% CI, 13% to 71%) of the attacks within 2 hours and in 77% (95% CI, 48% to 92%) within 4 hours. CONCLUSION: This is the first prospective study to show that intranasal or oral sumatriptan may be effective in patients experiencing moderate to severe headache attacks which consistently do not fulfill the IHS criteria for migraine or episodic tension-type headache.

Epidemiological aspects of headache in a workplace setting and the impact on the economic loss.

The objective of this study was to assess the epidemiological aspects of headache in a workplace setting and the economical impact. By sending a questionnaire to 1781 employees of a Dutch manufacturing company we tried to assess the prevalence of headache and headache subtype within this working place. Besides the personal view of each responder regarding his/her headache subtype, the International Headache Society (IHS) criteria were used to classify headaches on the basis of reported features. Moreover the missing labour days, as a result of headache, during the previous 4 weeks were measured, as well as the loss of productivity at the working place during an episode of headache; from this an estimate of the economic loss could be calculated. The response rate of the questionnaire was 60.8%. The lifetime prevalence of headache amongst the responders was 53.3%. Of these, 34.5% thought their headache was tension-type headache, 10.6% thought it was migraine, 5.4% mentioned daily headache, and 18.2% mentioned another type of headache. According to the IHS criteria the differentiation was somewhat different: 26.2% of the headache could be classified as tension-type headache and 15% as migraine. When the costs for lost labour days and loss of productivity as a result of all types of headache were accumulated, the economic loss was estimated at 18.933 US dollars in 4 weeks (for the group of responders). In conclusion, headache is related to a substantial economic loss; migraine is probably underestimated in a workplace setting.

In-vitro testing and the carcinogenic potential of several nitrosated indole compounds.

4-chloro-methoxyindole is a naturally occurring compound in Vicia faba which can easily react with nitrite to form a N-nitroso compound. In this in vitro study, the potential genotoxic effects of nitrosated 4-chloro-6-methoxyindole and its structural analogue 4-chloroindole were evaluated for the first time by using both Salmonella and Chinese hamster V79 cells. Additionally, the inhibition of gap junctional intercellular communication in V79 cells by these compounds was determined; this is a validated parameter for tumor-promoting activity. Most assays were also performed with nitrosated indole-3-acetonitrile, a naturally occurring compound in brassicas. Both nitrosated chloroindoles were highly mutagenic to Salmonella typhimurium TA100 without the need of exogenous metabolic activation and were potent inducers of Sister Chromatid Exchanges. Nitrosated indole-3-acetonitrile generated the same effects, although at much higher concentrations. Equivocal results were obtained for the nitrosated chloroindoles in a forward mutation assay using the hypoxanthine guaninephosphoribosyltransferase locus. All nitrosated indole compounds significantly inhibited gap junctional intercellular communication. These results indicate that nitrosated chloroindoles and nitrosated indole-3-acetonitrile should be considered as mutagens and agents with potential tumor-promoting capacity.

Stability of mutagenic nitrosated products of indole compounds occurring in vegetables.

Levels of indolylglucosinolates in Brassica vegetables correlated significantly with the amounts of N-nitroso compounds formed in these vegetables after nitrite treatment. Nitrosation of indole-3-carbinol, indole-3-acetonitrile and indole, hydrolysis products of an indolylglucosinolate, resulted in formation of nitrosated products, which were directly mutagenic to Salmonella typhimurium TA100. The nitrosated products were unstable at pH 2 but stable at pH 8. Experiments to elucidate the mechanisms behind these differences in stability showed an equilibrium between the nitrosated indole compound and the free compound plus nitrite.

Several known indole compounds are not important precursors of direct mutagenic N-nitroso compounds in green cabbage.

In this study we investigated the role of indole-3-acetonitrile, indole-3-carbinol, indole and tryptophan in the formation of N-nitroso compounds in green cabbage extracts. Green cabbage extracts were separated by gel permeation chromatography. Fractions were treated with nitrite, tested for mutagenicity and analysed for total N-nitroso content. Fractions in which spiked indole-3-acetonitrile, indole-3-carbinol, indole and tryptophan eluted appeared to be low in mutagenic activity and contained relatively small amounts of N-nitroso compounds. To detect indole compounds other than the ones used in the gel permeation chromatography experiments, high-performance liquid chromatography and gas chromatography-mass spectrometry analyses were performed of green cabbage extracts. Indole-3-carboxaldehyde was found to be the most commonly occurring indole compound, but it did not show direct mutagenic activity upon nitrite treatment. Indole-3-acetonitrile was the second most common compound; although it was mutagenic after nitrite treatment, its contribution to the mutagenicity of nitrite-treated green cabbage was roughly estimated to be only 2%. No other indole compounds were detected. From this study we conclude that neither the tested indole compounds nor indole-3-carboxaldehyde play a significant role in the formation of direct mutagenic N-nitroso compounds in nitrite-treated green cabbage extracts.

The stability of the nitrosated products of indole, indole-3-acetonitrile, indole-3-carbinol and 4-chloroindole.

The nitrosation rates of indole-3-acetonitrile, indole-3-carbinol, indole and 4-chloroindole and the stability of their nitrosated products were investigated. Each of the nitrosated indole compounds was directly mutagenic to Salmonella typhimurium TA100 in the following order of potency: 4-chloroindole much greater than indole-3-carbinol greater than or equal to indole greater than indole-3-acetonitrile. Total N-nitroso determinations, carried out according to a modified method of Walters et al. (Analyst, Lond. 1978, 103, 1127), and Ames test results revealed that each of the indole compounds immediately formed mutagenic N-nitroso products upon nitrite treatment under acidic conditions. However, the nitrosation rates of indole and 4-chloroindole were higher than those of indole-3-acetonitrile and indole-3-carbinol. For indole-3-carbinol, indole-3-acetonitrile and indole, no change in the amount of nitrosated products was observed at increasing incubation times from about 15 up to 60 min. For 4-chloroindole the amount of nitrosated products decreased with increasing incubation times. In all cases the responses in the Ames test paralleled the amounts of nitrosated products. The stabilities of the nitrosated products of the indole compounds were investigated at pH 2 and 8. Both mutagenicity data and measurements by high-performance liquid chromatography using a photohydrolysis detector indicated that the nitrosation products of indole-3-acetonitrile, indole-3-carbinol and indole were more stable at pH 8 than at pH 2. Conversely, nitrosated 4-chloroindole was stable at pH 2 but not at pH 8. The pH 8 chromatograms showed a large nitrite peak. From this we hypothesized that the presence of free nitrite might be responsible for the stability of nitrosated indole-3-acetonitrile, indole-3-carbinol and indole at pH 8. Experiments confirmed the existence of an equilibrium between the nitrosated indole compound and the free indole compound plus nitrite.

Variability in lipoprotein concentrations in serum after prolonged storage at -20 degrees C.

The effects of freezing and storage at -20 degrees C of serum on the measurement of cholesterol and triglycerides concentrations in lipoprotein fractions separated by density gradient ultracentrifugation were investigated. Fresh, fasting, normolipidemic sera from 24 healthy individuals were divided into aliquots and stored, using different conditions. After storage, serum lipoproteins were separated by density gradient ultracentrifugation, and cholesterol and triglycerides assayed enzymatically. Freezing as such had no effect on the concentration of cholesterol and triglycerides in the various lipoproteins; changes averaged 0.00 mmol/l (range, -0.02 to 0.02 mmol/l). The concentration of cholesterol in the major cholesterol fractions (LDL, HDL2 and HDL3) changed on average by less than 4.1% over the full period of 27 wk. The percentage changes in the triglyceride concentrations over the first 11 wk were less than 5% for the major triglyceride fractions (VLDL and LDL) except for LDL after 11 weeks of storage (change +9.4%). By 27 weeks of storage, triglyceride concentrations had changed by -13.0% in VLDL and by +13.0% in LDL. It is concluded that fasting normolipidemic serum can be stored at -20 degrees C for at least 11 wk before lipoproteins are separated by density gradient ultracentrifugation and analyzed for cholesterol and triglycerides.

Formation of mutagenic N-nitroso compounds in vegetable extracts upon nitrite treatment: a comparison with the glucosinolate content.

More than 30 vegetables were screened for their potential to form biologically active N-nitroso compounds upon treatment with nitrite under acidic conditions. The total N-nitroso content was determined in the nitrite-treated and untreated extracts of the vegetables according to a modified method of Walters et al. (Analyst, Lond. 1978, 103, 1127). All treated extracts contained N-nitroso compounds at levels ranging from 23 to 789 nmol/25 mg dry matter. In the same samples the mutagenic activity was determined using the Salmonella typhimurium assay. About half of the vegetables were found to be mutagenic upon nitrite treatment. (Nitrite-treated extracts were considered to be mutagenic if the number of induced revertants was at least twice as high as that induced by the corresponding untreated extract). The content of different glucosinolates in the dry matter of the vegetables was also determined. Glucosinolates could be detected only in cruciferous vegetables, at levels ranging from 1.8 to 26.0 mumol/g dry matter. Although the nitrite-treated extracts of brassica species contained more N-nitroso compounds and induced more revertants than did other vegetables, there was no significant correlation between these parameters. However, the amounts of N-nitroso compounds formed upon nitrite treatment (expressed per fresh weight) did correlate significantly (P less than 0.01) with the amounts of glucosinolates (r = 0.95). When the glucosinolates were divided into aryl/alkyl- and indolyl-glucosinolates, the significant correlation was maintained for both subgroups (r = 0.93 and 0.95, respectively). From this it can be concluded that glucosinolates are probably involved in the formation of N-nitroso compounds in certain nitrite-treated vegetables.

A co-cultivation system as a model for in vitro studies of modulating effects of naturally occurring indoles on the genotoxicity of model compounds.

An in vitro model system, consisting of primary chick embryo hepatocytes as the metabolizing system co-cultured with V79 Chinese hamster cells as the target cells for the SCE assay, was used to study the modulating effects of naturally occurring indoles on the genotoxicity of benzo[a]pyrene (B[a]P) and N-nitrosodimethylamine (NDMA). At 25 mug/ml, indole-3-carbinol (I3C) induced ethoxyresorufin-O-deethylase (ERROD) activity 3.9-fold and ethoxycoumarin-O-deethylase (ETCO) activity 2-fold. Indole-3-acetonitrile (I3A; 35 mug/ml) induced ERROD activity 1.6-fold and ETCO activity 2-fold. Pretreatment with I3C resulted in a 20-40% decrease in genotoxicity for both B[a]P and NDMA. Pretreatment with I3A resulted in a similar decrease in genotoxicity for B[a]P, whereas no decrease was observed for NDMA. When a microsomal fraction prepared from I3C-pretreated hepatocytes was used, no decrease in B[a]P-induced genotoxicity was found; in contrast, use of an S-9 fraction prepared from the same cells resulted in a 45% decrease. Exposure of cells to B[a]P after pretreatment with I3C for suboptimal times also resulted in a significant decrease in genotoxic activity. The data indicate that the protective effects of pretreatment with the indoles, observed in this study, are not directly correlated with induction of cytochrome P-450-associated enzymes. Instead they seem to be more the result of a changed balance in the enzyme systems involved in the indole biotransformation process and point to an essential role of conjugating enzyme systems.