Monitoring of aflatoxin exposure by biomarkers.

Epidemiological studies have demonstrated a strong association between exposure to AFB1 and an increased incidence of human hepatocellular carcinoma (HCC). This association has led to a need for accurate techniques relating AF exposure to an individual's risk of developing disease. With the understanding of the progressive processes of carcinogenesis, opportunities for the identification of molecular biomarkers reflecting events from exposure through clinical disease are provided. However, the development of biomarker methods to monitor human exposure to AFs requires techniques which are sensitive, specific, and amenable to large numbers of samples. To better understand the role of AF exposure with respect to HCC incidence, immunoassays for the biological quantitation of free AFB1, its metabolites, and its adduct macromolecules have been developed. ELISA appears to offer a suitable method for use in epidemiological studies for monitoring short-term exposure to AFs, as it has the appropriate sensitivity and specificity. However, the presence of substances that are presumably not AFs and which are inhibitory in the ELISA system has necessitated the development of purification techniques, usually based on adsorption onto Sep-Pak C18 cartridges and immunoaffinity chromatography. Many protocols have been developed for the assay of soluble AF metabolites in urine, milk and blood. However, these assays only indicate recent exposure, whereas the presence of albumin-AFB1 adducts in peripheral blood could present a useful material for assessing longer-term exposure. Among the various possible biomarkers of AF exposure, the measurements of AF-DNA and -protein adducts are of major interest because they are direct products of damage to a critical cellular macromolecular target. In Thailand, AF contamination of foods was reported to be high. More recent data using biomarkers as measures of AF exposure will be discussed. The data from epidemiological studies, AF exposure assessment using AF-albumin adduct and urinary AF level as exposure markers as well as the prevalence of p53 mutation at codon 249 are all suggestive of a limited importance of AF in the etiology of HCC in this country compared to other areas, including parts of Africa and China. These results also indicate that research on other potential hepatocarcinogens should not be neglected.

Impaired absorption of paracetamol in vegetarians.

1. The absorption and disposition of paracetamol was investigated in 10 healthy male Thai vegetarians and 10 similar non-vegetarians following an oral dose of 20 mg kg-1. 2. The absorption rate of paracetamol was significantly impaired in the vegetarians compared with the non-vegetarians as shown by a lower mean Cmax (11.7 +/- 1.4 vs 15.6 +/- 1.6 mg l-1; 95% confidence interval of the difference 2.49 to 5.36), increased tmax (median 1.75, range 0.75 to 3 h compared with 0.75 and 0.25 to 2 h) and an increase in the time for input of 50% of the total amount absorbed (0.54 +/- 0.38 compared with 0.20 +/- 0.10 h; 95% confidence interval of the difference 0.063 to 0.61). 3. A significantly lower total 24 h urinary recovery of paracetamol and metabolites (72.1 +/- 5.4 vs 86.4 +/- 5.4% of the dose; 95% confidence interval of the difference 8.0 to 20.6) indicated a decrease in the extent of absorption in the vegetarians also, although the total AUC values did not differ significantly between the two groups. 4. The plasma paracetamol half-life, partial metabolic clearances and fractional urinary excretion of the glucuronide, sulphate, cysteine and mercapturic acid conjugates of paracetamol were similar in the vegetarians and non-vegetarians.

Epidemiology and risk factors of injury in Thai children.

A case-control study was carried out to identify risk factors of injury in 200 children (mean age 6.68 +/- 3.9 years) attending the Emergency Room, Ramathibodi Hospital from April to August 1987. Traffic and falls were the most common causes of injuries in all age groups. Falls, traffic and sport injuries were responsible for the age-specific injury in infants, 1-10 years and more than 10 year-old children respectively. Most of the injuries occurred at home and on the street, during school term, working day, and between 3-8 pm. Twenty two percent of them needed hospitalization. Another 200 patients, matched sex and age range (mean age 6.38 +/- 3.8 year) from the general out patient department were selected as controls. Parents or care providers were interviewed. The result showed that boys, children older than 6 years of age not attending school, higher rank of order of the child in the family, large family size, the more care providers at the time, parental education lower than primary school level and low family income were risk factors of injury in these children (OR = 1.8, 2.4, 1.6-2.7, 1.7-3.3, 6.2, 2.1, 1.8 and 2.4 respectively).

Ethnic differences in the renal sodium dopamine relationship. A possible explanation for regional variations in the prevalence of hypertension?

Over the last three years we have carried out studies on the urine output of both sodium and dopamine in five different ethnic groups: whites, Ghanaians, Zimbabweans, Iranians and Thais. Sodium was measured by ion specific electrode and dopamine by HPLC with electrochemical detection (using epinine as an internal standard). In several groups salt loading studies were also carried out. The five ethnic groups differed substantially with regard to the correlation between their urinary sodium and dopamine outputs. Three groups (whites, Thais and Zimbabweans) showed a strong positive correlation (P less than .001) and this may reflect their traditionally salt rich diet. In two groups (Ghanaians and Iranians) there was no correlation and this may reflect a salt scarce environment. Taken together with our previously reported studies showing that normotensive Ghanaians do not mobilize dopamine on salt loading, this would suggest that certain ethnic groups are predisposed to develop hypertension on salt loading--that is, they are 'salt sensitive.' This genetic trait may have passed from the West Coast of Africa, with the slaves, to America and the Caribbean. Other workers have reported deficiencies in vasodilator systems in the American black, such as dopamine, kallikrein and the renal prostaglandins. These defects may lead to the nosologic entity of 'low renin' hypertension, well described in American blacks, and could open up avenues of therapy based either on DA1 activators (such as fenoldopam) or on renal prodrugs (such as gludopa).

Ethnic differences in the renal dopamine response to an oral salt load.

Dopamine is a natriuretic hormone which is synthesised within the kidney. We have previously found that some ethnic groups (e.g. British Caucasians and Thais) show strong positive correlations between 24 h urinary sodium and dopamine outputs. However no such relationship was found in Iranians and black West Africans. We have now studied the effect of oral salt loading (200 mmol) on 24 h urinary sodium and dopamine outputs in individuals from these four ethnic groups. The Caucasians showed a significant increase (35%) in urinary dopamine output after salt loading. However, there was no dopamine response to the salt load in the Ghanaians and the Iranians. The Thais were all vegetarians and fell into two distinct groups with either an increase ('positive responders') or decrease ('negative responders') in dopamine output after salt loading. The negative responders all had a very low mean control sodium output (60 +/- 21 mmol/24 h) compared to the positive responder Thais and the other three ethnic groups which all had mean sodium outputs greater than 115 mmol/24 h. We hypothesize that in some racial groups the uncoupling of the renal sodium-dopamine relationship may be an inherited mechanism to help conserve sodium (as in the Ghanaians and the Iranians) or an adaptive change to being restricted to a low salt diet for a long time (as in the Thai 'negative responders').

Ethnic differences in the renal sodium-dopamine relationship: a possible explanation for regional variation in the prevalence of hypertension?

Twenty-four-h urinary sodium and dopamine output by normotensive adults from 5 different ethnic groups have been measured. The groups differed substantially in the correlation between the urinary output to sodium and dopamine. Those with a traditionally salt rich diet (Thais, Caucasians, Zimbabweans) showed a strong positive correlation (p less than 0.001), whereas no such relationship was found in West Africans and Iranians, who come from traditionally salt scarce environments. It is hypothesised that in some races the lack of or uncoupling of the renal sodium-dopamine relationship, possibly as a mechanism to help conserve dietary sodium, predisposes to the development of hypertension when the individuals encounter a salt rich diet.

Further ethnic differences in the renal sodium-dopamine relationship: its uncoupling in Iranian but not in Thai normotensive subjects.

Dopamine is a natriuretic hormone and is synthesized in the kidney in response to a sodium load. This relationship results in a positive correlation between urinary sodium and dopamine outputs. Uncoupling of the renal sodium-dopamine relationship is reflected in a loss of this correlation and will result in the sluggish excretion of a sodium load. We measured 24-h urinary sodium and dopamine outputs in Thais and Iranians, who traditionally have very different dietary salt environments (salt-rich and salt-scarce, respectively). There was a highly significant positive correlation between sodium and dopamine in the Thais (r = 0.53, P less than 0.001) but no suggestion of such a correlation in the Iranians (r = 0.03). We hypothesize that in some races the uncoupling of the renal sodium-dopamine relationship, possibly as a mechanism to help conserve dietary sodium, predisposes the race to the development of hypertension when the individuals encounter a salt-rich diet.

Influence of caffeine on aspirin pharmacokinetics.

The effects of caffeine on the pharmacokinetics and bioavailability of aspirin were studied in 12 healthy adult male volunteers. The subjects received 650 mg of aspirin or 650 mg of aspirin with 120 mg of caffeine citrate orally. It was found that caffeine significantly increased the rate of appearance as well as the maximum concentration of salicylate in the plasma by about 25% and 17%, respectively. Moreover, area under the plasma concentration-time curve of salicylate was significantly higher in the subjects given the drug combination as compared to those given aspirin alone. There was no change in the plasma half-life, volume of distribution and clearance of salicylate.

Adverse reaction assessment in Thailand.

In Thailand, 5 years ago, the Ministry of Public Health set up the National Adverse Drug Reaction Monitoring Center for collecting, analysing and compiling all evidence related to drug hazards. Between March 1983 and December 1985, 790 reports on adverse drug reactions have been received, of which 711 could be analysed. Adverse drug reactions are commonly reported with the antibiotics, other anti-infective agents, analgesics and antipyretics, and anti-inflammatory drugs. Most of the reported reactions are related to skin reactions and gastrointestinal disorders. It is unquestionable that such voluntary reporting is more useful qualitatively than quantitatively. Even though there are a lot of problems facing us in assessing adverse drug reactions, it is a necessity to have the programme running and improving as time goes by. There is an urgent need for well-trained personnel to perform such tasks.

Thyrotropin (TSH)-induced hyperthyroidism: response of TSH to dopamine and its agonists.

A 12-yr-old girl with the syndrome of hyperthyroidism due to inappropriate TSH secretion, who had no evidence of pituitary tumor, was studied in detail. She had undergone two thyroidectomies for recurrent goiter and hyperthyroidism before referral. Basal serum TSH levels were extremely high (maximum 173 microU/ml), and the TSH response to TRH was exaggerated (peak, 675 microU/ml). The serum alpha-subunit of TSH was normal. PRL and other anterior pituitary hormone studies were normal. Dopamine infusion at 2 and 4 micrograms/kg X min partially suppressed TSH and PRL secretion and their responses to TRH. Bromocriptine had a paradoxical effect, resulting in an increase in TRH-stimulated TSH levels. Pergolide, a newer dopamine agonist, significantly decreased per basal serum TSH and blunted the TSH response to TRH; however, despite progressive dose increases, her TSH level was not reduced to normal.

Inhibition by acetyl-CoA of hepatic carnitine acyltransferase and fatty acid oxidation.

At micromolar concentrations, acetyl-CoA inhibited hepatic carnitine acyltransferase activity and mitochondrial fatty acid oxidation. The inhibitory effects were not nearly as potent on a molar basis as those of malonyl-CoA; nevertheless, the cytosolic concentrations of acetyl-CoA, as yet unknown, may be sufficient (greater than 30 microM) to curtail appreciably the mitochondrial transfer of long-chain acyl-CoA units and fatty acid oxidation. Hence acetyl-CoA may also partially regulate hepatic ketogenesis.

Evaluation of current clinical trial methodology in analgesimetry based on experts' opinions and analysis of several analgesic studies.

There is general agreement that the controlled clinical trial is the best method for analgesic evaluation. Current practice in clinical analgesimetry, however, varies considerably with regard to design, measurement of pain, and statistical analysis. We attempted to assess the degree of this diversity by a questionnaire survey of a sample of investigators who are currently conducting clinical pain studies. To examine how various statistical methods perform in practice, we reanalyzed data from four of our published analgesic studies using a number of standard methods.

Studies with different types of visual analog scales for measurement of pain.

We compared the sensitivity of different types of visual analog scales and of descriptive pain terms in healthy volunteers and in postoperative patients. One hundred and seven volunteers marked visual analog scales according to their perception of the descriptive pain terms--little, mild, some, moderate, severe, agonizing. Individual variation in values and preferences between the five following five different visual analog scales were analyzed: 10-cm linear horizontal and vertical scales, a curvilinear scale, and graded horizontal and curvilinear scales. Significantly more volunteers preferred the horizontal scale with gradations. Scores for the vertical linear scale had the greatest coefficient of variation and were least normally distributed. The majority of volunteers considered the phrase "agonizing pain" the best term defining the extreme limit of pain (X2(12) = 41.8, P less than 0.001). There were significant changes in the values of pain intensity measured on visual analog scales by patients using the same descriptive pain term on successive observations. However, the patients' values for pain terms in the preoperative pain-free state were not significantly different from those during postoperative pain. We conclude that graded linear horizontal scales are both more reliable and preferred by participants and that visual analog scales give a more sensitive and accurate representation of pain intensity than do descriptive pain scales.

Analysis of narcotic analgesic usage in the treatment of postoperative pain.

We reviewed 526 medical records of surgical patients and interviewed 81 of these patients. We also sent questionnaires to house staff (57 of 97 responded) and nurses (70 of 142 responded) involved in the care of these patients. A substantial number of patients suffered at least moderate pain during the postoperative period despite analgesic medication. Patients received 70% of the maximal ordered analgesic dose in the first 24 hours. Physicians prescribed drugs in doses that were often inadequate and to be given at inflexible intervals. The optimal doses and duration of action of meperidine, as judged by the house staff and nurses, did not agree with the accepted pharmacologic profile of this drug.