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Biomedical subjects

P Jacob

Publications and source records attributed to P Jacob.

At least 19 recordsLinked to original sources
PubMed1998

Nicotine metabolism and intake in black and white smokers.

CONTEXT: Racial differences in tobacco-related diseases are not fully explained by cigarette-smoking behavior. Despite smoking fewer cigarettes per day, blacks have higher levels of serum cotinine, the proximate metabolite of nicotine. OBJECTIVE: To compare the rates of metabolism and the daily intake of nicotine in black smokers and white smokers. DESIGN: Participants received simultaneous infusions of deuterium-labeled nicotine and cotinine. Urine was collected for determination of total clearance of nicotine and cotinine, fractional conversion of nicotine to cotinine, and cotinine elimination rate. Using cotinine levels during ad libitum smoking and clearance data, the daily intake of nicotine from smoking was estimated. SETTING: Metabolic ward of a university-affiliated public hospital. PARTICIPANTS: A total of 40 black and 39 white smokers, average consumption of 14 and 14.7 cigarettes per day, respectively, of similar age (mean, 32.5 and 32.3 years, respectively) and body weight (mean, 73.3 and 68.8 kg, respectively). MAIN OUTCOME MEASURES: Clearance (renal and nonrenal), half-life, and volume of distribution of nicotine and cotinine and the calculated daily intake of nicotine. RESULTS: The total and nonrenal clearances of nicotine were not significantly different, respectively, in blacks (17.7 and 17.2 mL x min(-1) x kg(-1)) compared with whites (19.6 and 18.9 mL x min(-1) x kg(-1)) (P=.11 and .20). However, the total and nonrenal clearances of cotinine were significantly lower, respectively, in blacks (0.56 and 0.47 mL x min(-1) x kg(-1)) than in whites (0.68 vs 0.61 mL x min(-1) x kg(-1); P=.009 for each comparison). The nicotine intake per cigarette was 30% greater in blacks compared with whites (1.41 vs 1.09 mg per cigarette, respectively; P=.02). Volume of distribution did not differ for the 2 groups, but cotinine half-life was higher in blacks than in whites (1064 vs 950 minutes, respectively; P = .07). CONCLUSIONS: Higher levels of cotinine per cigarette smoked by blacks compared with whites can be explained by both slower clearance of cotinine and higher intake of nicotine per cigarette in blacks. Greater nicotine and therefore greater tobacco smoke intake per cigarette could, in part, explain some of the ethnic differences in smoking-related disease risks.

Adult↗
PubMed1998

Thyroid dose and thyroid cancer incidence after the Chernobyl accident: assessments for the Zhytomyr region (Ukraine).

In the Zhytomyr region, about 52,000 measurements of the 131I activity in thyroids were performed. On the basis of these measurements, individual doses have been assessed for the people monitored and age-dependent average doses have been estimated for those settlements with more than 11 direct measurements. In order to estimate the pattern of thyroid exposure in the Zhytomyr region, these doses have been interpolated or extrapolated to population groups who were not monitored during May-June 1986. For this purpose, a model has been developed based on a correlation between thyroid dose estimates with the 137Cs deposition and the co-ordinates of the settlements relative to Chernobyl. Collective doses of people who were born in the years 1968 to 1986 were calculated. The radiation-induced thyroid cancer incidence in the period 1991 to 1995 was assessed by subtracting the spontaneous incidence from the observed incidence. The result is considerably lower than that observed in longer periods after external exposures. Possible reasons for this difference are discussed.

Adolescent↗
PubMed1998

Dose-related cardiovascular and endocrine effects of transdermal nicotine.

BACKGROUND: Transdermal nicotine in doses up to 21 mg/24 hr is used to facilitate smoking cessation. However, this dose does not achieve the nicotine plasma levels seen among heavy smokers, and underdosing may be one of the reasons for the limited efficacy of transdermal nicotine. There are some concerns about the adverse cardiovascular effects of nicotine, especially with concomitant smoking. Treatment with higher doses of transdermal nicotine has been proposed for highly dependent smokers, but the effects of such treatment on the cardiovascular system have not been determined. The objective of this study was to determine the cardiovascular effects of high-dose transdermal nicotine with concomitant smoking. METHODS: Twelve healthy male smokers received three doses of transdermal nicotine (21, 42, and 63 mg/24 hr) and placebo, each for 5 days, in a balanced order. The subjects smoked during the first 4 days of each treatment and abstained from smoking during the fifth day. Ambulatory 24-hour daytime and nighttime heart rate and blood pressure values were determined for each treatment; plasma nicotine, cotinine, and carboxyhemoglobin levels and urinary catecholamines with aldosterone were measured on days 4 and 5. The data were compared by means of repeated-measures ANOVA. RESULTS: There was no difference in heart rate or blood pressure and no changes in the pattern of circadian variations with various transdermal nicotine doses compared with smoking alone, consistent with the development of tolerance. Urinary epinephrine level was significantly higher (p < 0.05) with transdermal nicotine compared with no nicotine but was not higher with transdermal nicotine and smoking compared with smoking alone. No change was found in fibrinogen and lipid profiles with different nicotine doses. CONCLUSIONS: High-dose nicotine treatment, even with concomitant smoking, caused no short-term adverse effects on the cardiovascular system.

Administration, Cutaneous↗
PubMed1998

Issues in the reconstruction of environmental doses on the basis of thermoluminescence measurements in the Techa riverside.

The potential of thermoluminescence measurements of bricks from the contaminated area of the Techa river valley, Southern Urals, Russia, for reconstructing external exposures of affected population groups has been studied. Thermoluminescence dating of background samples was used to evaluate the age of old buildings available on the river banks. The anthropogenic gamma dose accrued in exposed samples is determined by subtracting the natural radiation background dose for the corresponding age from the accumulated dose measured by thermoluminescence. For a site in the upper Techa river region, where the levels of external exposures were extremely high, the depth-dose distribution in bricks and the dependence of accidental dose on the height of the sampling position were determined. For the same site, Monte Carlo simulations of radiation transport were performed for different source configurations corresponding to the situation before and after the construction of a reservoir on the river and evacuation of the population in 1956. A comparison of the results provides an understanding of the features of the measured depth-dose distributions and height dependencies in terms of the source configurations and shows that bricks from the higher sampling positions are likely to have accrued a larger fraction of anthropogenic dose from the time before the construction of the reservoir. The applicability of the thermoluminescent dosimetry method to environmental dose reconstruction in the middle Techa region, where the external exposure was relatively low, was also investigated.

Alpha Particles↗
PubMed1998

Evaluation of pharmacokinetic methods used to estimate caffeine clearance and comparison with a Bayesian forecasting method.

Simplified pharmacokinetic methods have been used to estimate caffeine clearance in subjects with liver disease. There is a need to have a reliable, easy to implement method for research and possible clinical use. This study evaluates the use of Bayesian pharmacokinetic forecasting techniques to estimate caffeine clearance and compares its performance to other published methods. Commonly used published methods include the two-concentration overnight salivary clearance method (Jost method) and a method that samples caffeine concentrations over a 4-hour time period (Nagel method). Both have been used in studies incorporating serial measurements of caffeine clearance to predict clinical outcomes in subjects with liver disease, but these approaches have not been proven useful. However, neither method has been formally evaluated for accuracy in estimating caffeine clearance in subjects with cirrhosis. The performance of the Jost, Nagel, and Bayesian methods was compared to a Gold Standard method that accurately measured caffeine clearance in healthy subjects and subjects with cirrhosis using an intravenous infusion of stable isotope-labeled caffeine. The Bayesian method, even when only one measured concentration of caffeine was used, was more accurate, better correlated to the Gold Standard method, and had less intraindividual variation than the two previously published methods. Before the idea of using serial measurements of caffeine clearance for clinical usefulness is rejected, a reevaluation using methods of estimating caffeine clearance that are more accurate than previous paradigms is needed.

Bayes Theorem↗
PubMed1998

Monte Carlo simulation of the production of short DNA fragments by low-linear energy transfer radiation using higher-order DNA models.

A realistic DNA target model has been developed and implemented in the biophysical simulation code PARTRAC. It describes five levels of the B-DNA structure (nucleotides, DNA helices, nucleosomes, chromatin fiber structure and chromatin fiber loops) on an atomic level for the whole genome inside a mammalian cell nucleus. The model is capable of describing regular solenoidal, crossed-linker or zigzag structures as well as repeating stochastic arrangements of nucleosomes in the chromatin fiber. Electron tracks resulting from monoenergetic electrons with energies up to 100 keV and from 220 kVp X rays, starting at random positions in the cell, were superimposed on four DNA target models with different chromatin fiber structures. The yields of SSBs, DSBs and short single- and double-stranded DNA fragments were determined from spatial coincidences with strand atoms. Two parameters of the model-the energy necessary to create an SSB and the distance between two breaks that would be scored as a DSB-were adapted to equate simulated and measured strand break yields after X irradiation of human fibroblast cells. The integral fractions of short single- and double-stranded fragments were rather similar for all condensed chromatin fiber structures; they agreed with experimental data for DNA fragments below 2 kbp. The simulated fragment size distributions in the range from 0.1 to 1.5 kbp reflected the fiber structure irrespective of strandedness or electron energy. The distributions using a stochastic arrangement of nucleosomes in the chromatin fiber were found to be in better accordance with experimental data than those obtained with regular fiber structures.

DNA↗
PubMed1997

Primary hepatocellular carcinoma in workers exposed to vinyl chloride: a report of two cases.

BACKGROUND: Vinyl chloride (VC), an industrial toxic gas, has a dose-dependent carcinogenicity in rodents and has been responsible for multiple cases of liver angiosarcoma in humans. The aim of this study was to describe histopathologic liver alterations and to evaluate risk factors for hepatocellular carcinoma in two workers from the same plant, both of whom had primary nonangiosarcoma liver tumors and were exposed to VC. METHODS: Clinical, biochemical, serologic, and pathologic data were reviewed at the time of hepatic resection. Clinical and biologic follow-up were available for several years before the diagnosis of hepatocellular carcinoma. RESULTS: Liver alterations distant from the tumor site were compatible with ongoing exposure to VC in both cases. Several areas containing dysplastic hepatocytes were present in nontumoral liver in one patient. Both patients are alive after partial liver resection, and 1 has had 5 years of follow-up without recurrence. CONCLUSIONS: Exclusion of classic risk factors for noncirrhotic hepatocellular carcinoma of the liver in both patients suggests a relationship between VC exposure and observed tumors. Systematic long term follow-up with biology and ultrasonography for workers exposed to VC may result in relatively early diagnoses of liver tumors and long term survival in some cases.

Carcinoma, Hepatocellular↗
PubMed1997

137Cs mobility in soils and its long-term effect on the external radiation exposure.

To predict the external gamma-dose rate of Chernobyl-derived 131Cs for a period of about 100 years after its deposition, the vertical distribution of radiocesium in several meadow soils in the Chernobyl area and in Germany was determined, and the corresponding residence half-times of his radionuclide in the various soil layers were evaluated using a compartment model. The resulting residence half-times were subsequently used to calculate the vertical distribution of 137Cs in the soil as a function of time and finally to predict the external gamma-dose rates in air for these sites at various times. A regression analysis of the data obtained showed that the time dependence of the relative gamma-dose rate in air D(t) at the Chernobyl sites can be described by an exponential equation D(t) = a + b x exp (-t/c), where t is the time after deposition. For the ten German sites the best fit was obtained using the two-exponential equation D(t) = a x exp(-t/b) + c x exp(-t/d). The gamma-dose rate of 137Cs at the Chernobyl sites decreases significantly more slowly with time than at the German sites. This means that after e.g. 30 years the mean relative gamma-dose rate at the German sites will have decreased from 100% (corresponding to an infinite plane source on a smooth surface) to 9% (95% confidence interval 8%-10%), while at the sites in the Chernobyl area it will have decreased only to 21% (20%-23%). This difference is the result of the longer residence half-times of 137Cs in the soils at the Chernobyl sites. All results are compared with estimates from earlier studies.

Cesium Radioisotopes↗
PubMed1997

Exact solutions of the clonal expansion model and their application to the incidence of solid tumors of atomic bomb survivors.

We derive explicit hazard functions for the clonal expansion model in the "exact formulation" and in the "epidemiological approximation" for the spontaneous rate and for short-time exposure. We investigate which combination of the biological parameters can be determined from the incidence function, and which cannot. We then analyze the incidence data of all solid tumors of atomic bomb survivors (1958-1987). We restrict ourselves to adults at exposure (> 20 years) and to attained age (< 80 years, and we consider the two cities (Hiroshima and Nagasaki) and the two sexes separately. With four parameters, we find good fits in each case, comparable to the quality of fit of epidemiological age-at-exposure and age-attained models used for comparison. The parameters which describe the spontaneous risk agree very well for the two cities, while they are quite different for the two sexes. The apparent flattening of the risk for elderly men can be described with the exact formulation of the clonal expansion model, but may be due to other causes than the mechanisms modeled. The dose-response parameters differ by more than two standard deviations (factor 2 to 3) between the two cities, when considering the same sex. They are bigger of the men of Nagasaki and the women of Hiroshima. One example for model application to tumors of specific organs (men's lung tumor) is considered.

Adult↗
PubMed1997

Thyroid cancer incidence in the Ukraine after the Chernobyl accident: comparison with spontaneous incidences.

The thyroid cancer incidence in the Ukraine among those born in the period 1968-1986 was analyzed with the aim to identify the enhancement due to the Chernobyl accident. Since any Ukrainian data referring to the time period before the accident are scarce and the variation of spontaneous incidences in other countries is immense, the Ukrainian incidences in the period 1986-1989 were used to estimate the baseline risk. Following 1990, the incidence in the southern part of the Ukraine increased by about 30%, independent of age. In the other parts the increase of the incidence depended on age at exposure. In the age group of 9-year-old children, the incidences in three regions defined as the 'high-dose area', the northern, and the middle oblasts, increased by factors of 50, 20, and 6, respectively. These rates (1991-1995) are well above spontaneous rates in other countries. In the age group of 17-year-old juveniles, the incidence increased by a factor of 6 for the 'high dose area' and in the three northern oblasts, whereas in the nine 'middle' oblasts it was similar to the incidence of the 'southern' Ukraine. These rates are within the range found in other countries.

Adolescent↗
PubMed1997

Cotinine effects on nicotine metabolism.

BACKGROUND: Nicotine clearance and half-life are known to be significantly reduced in smokers compared to nonsmokers. Cotinine is the major primary metabolite of nicotine, and it accumulates in the body with regular smoking. Nicotine and cotinine appear to be metabolized by the same liver enzyme. Therefore we hypothesized that cotinine inhibits nicotine metabolism, resulting in slower nicotine clearance in smokers compared with nonsmokers. METHODS: This was a crossover, randomized, double-blind, and placebo-controlled study. The subjects were 12 healthy nonsmoking volunteers. They received two intravenous infusions of deuterium-labeled nicotine-d2 and cotinine-d4 (0.5 micrograms/kg/min), once with oral cotinine treatment of 0.25 mg/kg twice a day and once with placebo. Nicotine and cotinine pharmacokinetic parameters were determined for each infusion. RESULTS: During oral cotinine treatment, average plasma levels of cotinine ware 900 ng/ml, comparable to levels observed in some very heavy smokers. Cotinine had no effect on the disposition kinetics of nicotine-d2. The half-life of cotinine after low-dose cotinine-d4 infusion was comparable to that after high-dose cotinine described in previous studies. The half-life of labeled cotinine derived from nicotine was significantly longer than the half-life of cotinine administered as cotinine. CONCLUSIONS: Cotinine is not responsible for the lower nicotine clearance observed in smokers. Our data suggest that the pharmacokinetics of low-dose cotinine in nonsmokers do not differ from those of high-dose in smokers, and therefore cotinine levels can be used quantitatively in environmental tobacco exposure. The longer half-life of cotinine derived from nicotine suggests that slow release of nicotine from tissues is responsible for the apparent long half-life of cotinine in nonsmokers exposed to environmental tobacco smoke.

Adult↗
PubMed1997

Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking.

AIMS: Nicotine nasal spray and transdermal nicotine are effective aids to smoking cessation, and are being evaluated for treatment of other medical diseases. Wide variation in levels of nicotine and its metabolite, cotinine, have been observed with such therapies. This study aimed primarily to assess sources of individual variability in nicotine and metabolite plasma levels from these dosing systems and from cigarette smoking. METHODS: Twelve cigarette smokers, studied on a clinical research ward, received four treatments of 5 days duration each, including (1) cigarette smoking, 16 cigarettes/day; (2) transdermal nicotine, 15 mg/day; (3) nicotine nasal spray, 24-1 mg doses/day; (4) placebo nicotine nasal spray, 24 doses/day. On a different occasion, the disposition kinetics of nicotine and cotinine were determined via infusion of deuterium-labeled nicotine and continine. Plasma levels of nicotine, cotinine, and 3'-hydroxycotinine and daily intake of nicotine during various treatments were examined, as well as pharmacokinetic factors that determined plasma nicotine and continine levels. RESULTS: There was considerable individual variation in plasma nicotine and cotinine levels and in the daily of nicotine absorbed from various delivery systems, with most variability with nicotine nasal spray (fivefold) and least for transdermal nicotine (two-to threefold). Plasma nicotine levels were determined most strongly by nicotine clearance. Continine levels were determined most strongly by dose of nicotine and, to a lesser extent, the clearance of cotinine and fractional conversion of nicotine to continine. CONCLUSIONS: Plasma levels of nicotine and cotinine produced by nicotine therapies are highly variable, due to both wide variability in individual pharmacokinetics and in dose delivery from the products. To compensate for individual differences in clearance, individualization of nicotine dosing based on therapeutic drug monitoring with comparison to nicotine or continine levels during cigarette smoking prior to treatment may be necessary to optimize nicotine therapy. This study also validates a recently proposed method for estimating absolute bioavailability of a drug using drug and metabolite pharmacokinetic data, and presents novel data on plasma levels of the metabolite trans-3'-hydroxycotinine in people.

Administration, Cutaneous↗
PubMed1997

Bioavailability of sublingual buprenorphine.

Buprenorphine administered sublingually is a promising treatment for opiate dependence. Utilizing a new, sensitive, and specific gas chromatographic electron-capture detector assay, the absolute bioavailability of sublingual buprenorphine was determined in six healthy volunteers by comparing plasma concentrations after 3- and 5-minute exposures to 2 mg sublingual and 1 mg intravenous buprenorphine. The amount of unabsorbed buprenorphine in saliva was measured after 2-, 4-, and 10-minute exposures to 2 mg sublingual buprenorphine in 12 participants. Pharmacokinetic parameters were analyzed by analysis of variance; bioequivalence was evaluated by the Schuirmann two-sided test. The 3- and 5-minute sublingual exposures each allowed 29 +/- 10% bioavailability (area under the plasma concentration-time curve unextrapolated) and were bioequivalent. Buprenorphine recovered from saliva after 2-, 4-, and 10-minute exposures was, on average, 52% to 55% of dose. Increased saliva pH was correlated with decreased recovery from saliva. Study results indicate that bioavailability of sublingual buprenorphine is approximately 30%. Sublingual exposure times between 3 and 5 minutes produce equivalent results. Buprenorphine remaining in saliva causes an almost twofold overestimation of bioavailability.

Administration, Sublingual↗
PubMed1997

Saliva cotinine levels as a function of collection method.

Saliva cotinine is commonly used to estimate nicotine intake but laboratories use different methods of collection. In three small trials, comparisons were made between (1) sugar vs. unstimulated saliva production (n = 29), (2) wax chewing vs. unstimulated production (n = 15) and (3) between two consecutive unstimulated saliva samples (n = 10). Sugar-stimulated saliva cotinine scores were 26% below unstimulated levels (p < 0.001); correlation between measures was high (r = 0.90; p < 0.001). Wax stimulated saliva yielded levels 6% below unstimulated (p < 0.05; correlation: r = 0.98; p < 0.001). No differences were observed between two unstimulated samples taken within a approximately 20-minute period (correlation: r = 0.99; p < 0.001). It is postulated that changes in salivary flow can account for the findings.

Biomarkers↗