Volatile nitrosamines and tobacco-specific nitrosamines in the smoke of Thai cigarettes: a risk factor for lung cancer and a suspected risk factor for liver cancer in Thailand

In Thailand, smoking of commercial cigarettes and of handmadecigarettes has drastically increased in recent decades. Cancerof the lung and of the upper aerodigestive tract have also increasedin Thailand as they have in many other countries. It is ourworking hypothesis that the increase of primary cancer of theliver, especially of cholangiocarcinoma in the north-easternprovinces of Thailand is associated with the use of tobaccoin men infested with the liver fluke Opisthorchis viverrini(OV). Bioassays have shown that volatile nitrosamines and tobacco-specificnitrosamines induce cholangiocarcinoma in laboratory animalsand that the hepatocarcinogenic action of nitrosodimethylaminein hamsters is significantly increased by infestation with theliver fluke OV. The endogenous formation of nitrosamines issignificantly increased by OV infestation. This report presentsanalytical data on the concentration of volatile nitrosaminesand tobacco-specific nitrosamines in mainstream smoke of nineleading brands of commercially produced Thai cigarettes whichrepresent ~85% of the market share in Thailand. Observed ranges(ng/cigarette) were 8.5–31.9 for nitrosodimethylamine,8.8–49.6 for nitrosopyrrolidine and 4.2–18.9 fornitrosodi-n-butylamine. These values are exceptionally highcompared with the smoke of light and blended cigarettes fromNorth America and Western Europe. Among the tobacco-specificnitrosamines, the range was 28–730 for nitrosonornicotineand 16–370 for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.There was a correla-tion between volatile and tobacco-specificnitrosamines, and tar and nicotine deliveries in the mainstreamsmoke. The analytical data are in line with the rate for lungcancer and support our working hypothesis that nitrosamines,and especially the tobacco-specific nitrosamines, are associatedwith the increased risk for primary liver cancer among thoseThai people who smoke cigarettes and also carry OV infestation.     

Rising leukemia rates in Thailand: the possible role of benzene and related compounds in cigarette smoke

Epidemiological studies suggest that cigarette smoking is associated with an increased risk of leukemia and that benzene and related compounds in cigarette smoke may contribute to this elevated risk. This report presents new findings on selected components of cigarette smoke (including benzene and 1,3-butadiene) from major brands of cigarettes sold in Thailand, which represent about 80% of market share. Tested were also two major and popular brands of U.S. cigarettes sold in Thailand, representing about 100% of market share. The cigarettes tested were filter and non-filter, and with high and 'low' tar and nicotine levels. The observed range for benzene, toluene and 1,3-butadiene were found in the range of 25.5-63.7, 36.4-79.8 and 44.6-78.7 microg/cigarette, respectively. The amount of acrolein ranged from 79.9-181 microg/cigarette and for isoprene from 313-694 microg/cigarette. Yields of these substances showed no correlation with tar deliveries in mainstream smoke. Consumption of tobacco products increased in Thailand since 1970. This study also showed increases in leukemia mortality rates in Thailand, and in the relative frequency of leukemia among incident cancers diagnosed at a large hospital in Bangkok. Exposure to benzene and related compounds in cigarette smoke may have contributed to these trends. Analytic epidemiological studies are needed on the relationship between these compounds in smoke from tobacco products used in Thailand. These preliminary findings support the need for voluntary and/or government-regulated reduction in smoke yields of benzene and related compounds in tobacco products, and for expanded smoking prevention and cessation efforts, in Thailand.     

Exposure to N-nitroso compounds in a population of high liver cancer regions in Thailand: volatile nitrosamine (VNA) levels in Thai food.

The recent case-control studies in Thailand indicate that a high incidence of liver cancer in Thailand has not been associated with common risk factors such as hepatitis B infection, aflatoxin intake and alcohol consumption. While the infestation by the liver fluke Opisthorchis viverrini (OV) accounted for the high risk in north-east Thailand, there was no such exposure in the other regions of the country where the incidence of liver cancer is also high. Case-control studies suggest that exposure to exogenous and possibly endogenous nitrosamines in food or tobacco in betel nut and cigarettes may play a role in the development of hepatocellular carcinoma (HCC), while OV infestation and chemical interaction of nitrosamines may also be aetiological factors in the development of cholangiocarcinoma (CCA). Over 1800 samples of fresh and preserved food were systematically collected and tested between 1988 and 1996. All the food items identified by anthropological studies to be consumed frequently in four major regions of Thailand were analysed for volatile nitrosamines using gas chromatography combined with a thermal energy analyser. Relatively high levels of N-nitrosodimethylamine (NDMA), N-nitrosopiperidine (NPIP) and N-nitrosopyrrolidine (NPYR) were detected in fermented fish ("Plasalid"). NDMA was also detected at levels ranging from trace amounts to 66.5 microg/kg in several salted and dried fish ("Larb-pla" and "Pla-siu"). NDMA and NPYR were frequently detected in several vegetables, particularly fermented beans ("Tau-chiau") at levels ranging between 1 and 95.1 microg/kg and 0-146 microg/kg, respectively. The possible role of nitrosamines in Thai food in the aetiology of liver cancer (HCC, CCA) is discussed.     

9‐Hydroxyrisperidone‐Induced Hyperprolactinaemia in Thai Children and Adolescents with Autism Spectrum Disorder

Although our previous study revealed an association between prolactin level and risperidone dosage, data regarding the plasma concentration of risperidone are lacking. Therefore, this study aimed to investigate the association between plasma drug concentrations of risperidone, 9‐hydroxyrisperidone and serum prolactin level in Thai children and adolescents with autism spectrum disorder (ASD). The individuals for this study were 103 children and adolescents with ASD (90 males and 13 females). In the 12th hour after the last risperidone dose, blood samples were collected for analysis. Serum prolactin, plasma risperidone and 9‐hydroxyrisperidone levels were measured. Patients' clinical data were collected from medical records – age, weight, height, body mass index, dose of risperidone and duration of treatment. Serum prolactin level was significantly positively correlated with plasma 9‐hydroxyrisperidone level (r_s = 0.355, p < 0.001). The median concentration of 9‐hydroxyrisperidone in individuals with hyperprolactinaemia (7.59 ng/ml; IQR 4.86–15.55) was significantly higher than non‐hyperprolactinaemic individuals (5.18 ng/ml; IQR 2.10–8.99) after risperidone treatment (p = 0.006). By multivariate analysis, high prolactin level was correlated to high 9‐hydroxyrisperidone level (p = 0.010). The results of this study showed that serum prolactin levels, especially in autistic individuals with hyperprolactinaemia during risperidone treatment, were significantly correlated with the level of 9‐hydroxyrisperidone. These results suggest that hyperprolactinaemia may develop during risperidone treatment.     

Combination chemotherapy for advanced lung cancer

Lung cancer is now a major public health problem in Thailand. This study was undertaken to gain some preliminary data regarding the potential effectiveness in treating advanced non-small cell lung carcinoma (NSCLC) using an ifosfamide combination therapy IA(E)P. A clinical study was made of all 50 patients (Thais) with histologically proven, advanced NSCLC admitted to the University of Siriraj Hospital between 1985 and 1987 and followed up until February 1992. Survival was calculated for responders and non-responders as distinct groups, and for the different histological tumors among the responders. There were 22 cases of adenocarcinoma, 13 large cell carcinoma, and 15 squamous carcinoma. Twenty-seven out of 50 (54%) responded to treatment. The median survival of the response group was 17 months, compared with 5.5 months in the nonresponse group. The longest survival period was seen in patients with large cell carcinoma. The results suggest that moderate success might be expected in selected patients using the IA(E)P. Further work should be undertaken in developing countries using controlled clinical trials to more fully determine the efficacy of IA(E)P in treating NSCLC.     

Microsatellite alterations in non-small cell lung cancer

Genetic alterations at 12 dinucleotide repeat loci located on human chromosomes 2, 3, 12, and 17 have been analyzed in non-small cell lung cancer from Thai patients. Seventeen out of 30 cases (57%) harbored the microsatellite alterations. Of the 30 cases, 19 patients had a history of tobacco smoking, of whom 14 (74%) were in the group with microsatellite alterations, whereas 3 out of 11 non-smokers (26%) had these alterations. The frequency of microsatellite alterations among smokers was significantly higher than it was in non-smokers (P = 0.01 Fisher's exact test; odds ratio; 7.47).     

Pharmacogenetics of Risperidone‐Induced Insulin Resistance in Children and Adolescents with Autism Spectrum Disorder

The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body‐weight and height. Genotyping was performed by TaqMan real‐time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852) and *41 (rs28371725), ATP‐binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642) and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag‐SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) ‐2548G>A (rs7799039), ghrelin gene (GHRL) ‐604G>A (rs27647) and brain‐derived neurotrophic factor (BDNF) 196G>A (rs6265)). Drug levels were analysed by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The results revealed that 5 (5.62%) patients presented with hyperglycaemia. Insulin resistance was detected in 15 (16.85%) patients. Insulin resistance was associated with LEP 2548 G>A and BDNF 196 G>A polymorphism (p = 0.051 and p = 0.03). There was no association of pharmacokinetic gene polymorphisms (CYP2D6 and ABCB1) and risperidone levels with insulin resistance. Multiple regression analysis indicated that BDNF 196 G>A polymorphism was significantly associated with insulin resistance (p = 0.025). This finding suggested that BDNF 196 G>A polymorphism may be a genetic marker for predicting insulin resistance before initiating treatment in patients treated with risperidone. Because of the small sample size, further studies are needed to confirm these results.     

Vinegar-processed Curcuma phaeocaulis promotes anti-angiogenic activity and reduces toxicity in zebrafish and rat models

ContextProcessing with vinegar could enhance the efficacy and reduce the toxicity of Curcuma phaeocaulis Valeton. (Zingiberaceae), a Chinese herbal medicine with anti-inflammatory and antitumor activities.ObjectiveThis study investigated the vinegar processing effects by evaluating anti-angiogenic effect and toxicity of C. phaeocaulis through zebrafish and rat models.Materials and methodsZebrafish embryos (AB and FLk-GFP strain) were applied to evaluate toxicity, cardiotoxicity and anti-angiogenic activity of volatile oil, and water decoction of the raw and vinegar-processed C. phaeocaulis. Meanwhile, a blood stasis syndrome rat model was applied to study the toxicity by measuring the ovarian and uterine coefficient.ResultsCurcuma phaeocaulis volatile oil and its vinegar-processed products in zebrafish had an LC₅₀ of 67.315 and 95.755 μg/mL, respectively. Curcuma phaeocaulis water decoction and its vinegar-processed products had an LC₅₀ of 161.440 and 206.239 μg/mL, respectively. The toxicity of vinegar-processed products was significantly lower than the raw, and the development characteristic of zebrafish embryos at different times confirmed these results. The volatile oil of vinegar-processed products could inhibit the growth of intersegmental blood vessels at the dose of 20 μg/mL, while the raw materials did not exhibit such effect at the same concentration. The rat experiment also confirmed that the volatile oil could reduce toxicity of ovarian and uterine.Discussion and conclusionsThe study indicated that processing using vinegar could decrease toxicity and increase anti-angiogenic activity of C. phaeocaulis, which could be applied for clinical treatment. Further in-depth study on the synergism and detoxification mechanism of vinegar processing technology is needed.