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M Rowland

Publications and source records attributed to M Rowland.

At least 73 records · Page 4Linked to original sources
PubMed1998

Estimation of specific hepatic arterial water space.

The aim of this study was to estimate the specific arterial water space and associated blood flow using statistical moments of the frequency versus time outflow profile, with a model with specific spaces for hepatic arterial (HA) and portal venous (PV) flows in parallel with a common space. Studies were performed in the in situ dual-perfused rat liver (n = 6-10), using Krebs-bicarbonate buffer with constant PV flow (12 ml/min) and various HA flow rates (3-6 ml/min). An impulse input-output technique was employed, varying the route of input, using [14C]urea as the reference indicator. Regardless of flow conditions, the frequency outflow profile after HA input was flatter and broader and the mean transit time longer than after PV input. Excellent recovery of marker was obtained in all cases. Applying the above model, the specific arterial space was estimated to be 9.7 +/- 2.3 of total water space and receives approximately 17% of the HA flow, with the remainder mixing with portal blood in the common space. The estimated total water content of liver (0.67-0.72 ml/g liver) agrees well with that determined by desiccation (0.72 +/- 0.01 ml/g liver).

Animals↗
PubMed1998

Is the risk of diabetic retinopathy greater in non-Hispanic blacks and Mexican Americans than in non-Hispanic whites with type 2 diabetes? A U.S. population study.

OBJECTIVE: To compare the risk for diabetic retinopathy in non-Hispanic white, non-Hispanic black, and Mexican-American adults with type 2 diabetes in the U.S. population. RESEARCH DESIGN AND METHODS: Representative population-based samples of people aged > or = 40 years in each of the three racial/ethnic groups were studied in the 1988-1994. Third National Health and Nutrition Examination Survey (NHANES III). Diagnosed diabetes was ascertained by medical history interview, and undiagnosed diabetes by measurement of fasting plasma glucose. A fundus photograph of a single eye was taken with a nonmydriatic camera, and a standardized protocol was used to grade diabetic retinopathy. Information on risk factors for retinopathy was obtained by interview and standard laboratory procedures. RESULTS: Prevalence of any lesions of diabetic retinopathy in people with diagnosed diabetes was 46% higher in non-Hispanic blacks and 84% higher in Mexican Americans, compared with non-Hispanic whites. Blacks and Mexican Americans also had higher rates of moderate and severe retinopathy and higher levels of many putative risk factors for retinopathy. Blacks had lower retinopathy prevalence among those with undiagnosed diabetes. In logistic regression, retinopathy in people with diagnosed diabetes was associated only with measures of diabetes severity (duration of diabetes, HbA1c, level, treatment with insulin and oral agents) and systolic blood pressure. After adjustment for these factors, the risk of retinopathy in Mexican Americans was twice that of non-Hispanic whites, but non-Hispanic blacks were not at higher risk for retinopathy. These risks were similar when people with undiagnosed diabetes were included in the logistic regression models. CONCLUSIONS: The prevalence and severity of diabetic retinopathy is greater in non-Hispanic blacks and Mexican Americans with type 2 diabetes in the U.S. population than in non-Hispanic whites. For blacks, this can be attributed to their higher levels of risk factors for retinopathy, but the excess risk in Mexican Americans is unexplained.

Adult↗
PubMed1998

Physiologically based pharmacokinetics of cyclosporine A: extension to tissue distribution kinetics in rats and scale-up to human.

The tissue distribution kinetics of i.v. Cyclosporine A (CyA) was investigated extensively in rats. The concentration-to-time data of 11 organs were analyzed separately using local physiologically based pharmacokinetic models, involving nonlinear plasma-to-blood cell distribution, membrane-permeability-limited plasma-to-tissue distribution and either linear or nonlinear tissue binding. Two global physiologically based pharmacokinetic models were then evaluated, each comprising arterial and venous pools together with the 11 organs, adopting either of the two local models. Both global models successfully described the blood and tissue distribution kinetics of CyA. In nonlinear model, the estimated dissociation constants (Kd) for the intracellular saturable binding ranged 0.2 to 60 ng/ml among the organs, which are comparable with values reported for cyclophilin-CyA binding in vitro. The predicted human pharmacokinetic profile using the physiologically based pharmacokinetic models, after scale-up of physiological parameters from rat to human, generally agreed with the observations following i.v. and oral administration, with moderate discrepancies due presumably to uncharacterized species differences and/or the effect of i.v. vehicle on the CyA binding in plasma. Nevertheless, the models allow reasonable prediction of drug exposure at the biological target, i.e., intracellular, unbound CyA, which may differ among various organs according to the local physiological elements, e.g., tissue cellular membrane permeability. As well as helping optimize the CyA regimen in patients, who are likely to exhibit a variety of physiological and pathological conditions, the modeling suggests possible insights into the known grafted-organ specific efficacy of CyA.

Animals↗
PubMed1998

[European Program for Intervention Epidemiology Training (EPIET): a training epidemiologic intervention in Europe].

The European programme for interventional epidemiology training (EPIET) offers a two year practical training in European national institutes mandated for the surveillance and control of communicable diseases. The training, closely supervised by senior epidemiologists, allows each EPIET fellow to learn while serving and conducting tasks devoted to intervention epidemiologists (surveillance, investigation, research, aid to decision making, and communication with the public, the media, the health authorities and the scientific community). The programme is equally funded by the European Commission, the 15 member states, Norway and the World Health Organisation. This training, derived from the North American and British experiences offers a practical complement to knowledge acquired from European universities. EPIET fellows, their supervisors and colleagues from training institutes have rapidly formed a network of intervention epidemiologists necessary for conducting and coordinating the surveillance of communicable diseases in Europe.

Communicable Diseases↗
PubMed1997

Carbon 13-labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.

Helicobacter pylori infection is mainly acquired in childhood, and studies on the epidemiology of this infection depend on the availability of a noninvasive diagnostic test for use in children. The aim of this study was to determine whether the carbon 13-labeled urea breath test (UBT) can be used in children by evaluating: (1) its sensitivity and specificity compared with either culture or both rapid urease test and histologic examination, (2) whether a test meal or a prolonged fast is required, (3) the usefulness after treatment for H. pylori. Eighty-eight children (mean age, 10.6 +/- 4.19 years) who were undergoing upper endoscopy were studied while fasting, not fasting, and after treatment. Children were given 50 mg of 13C-urea if they weighed less than 50 kg or 75 mg of 13C-urea if they weighed more than 50 kg with 50 mg of a glucose polymer solution in 7.5 ml of water. Breath samples were collected at baseline and at 15, 30, 45, and 60 minutes. In 63 fasting children the UBT was 100% sensitive and 97.6% specific at 30 minutes with a cutoff value of 3.5 delta 13CO2 per mil. Nonfasting tests in 23 children, performed between 1 and 2 hours after their usual meal, were 100% sensitive and 91.6% specific. In 13 children fed directly before the UBT, the sensitivity of the test was reduced to 50%. Thirty minutes was the optimal sampling time. There was a significant decrease in specificity when samples were obtained at 15 minutes, possibly caused by the interference of oral urease-producing organisms. The test was 100% sensitive and specific in 20 children after treatment for H. pylori infection. The UBT is a highly sensitive and specific test for the diagnosis of H. pylori infection in children. Neither a prolonged fast nor a test meal is required.

Adolescent↗
PubMed1997

Tissue water content in rats measured by desiccation.

Tissue water content was determined by desiccation to constant weight at 40 degrees-50 degrees C in 14 tissues from two groups of rats weighing 200-250 and 270-430 g, respectively. The water content (mean +/- SE; ml/g) was highest in testes (0.861 +/- 0.002) and lowest in adipose (0.183 +/- 0.017) followed by bone (0.446 +/- 0.017) and skin (0.651 +/- 0.007). The average water content in the remaining tissues was 0.763 (+/- 0.003). Upon correction for the water content of residual tissue blood, significant difference between the uncorrected and corrected tissue water was observed for spleen, lungs, kidneys, heart, liver, and brain. Tissue water was independent of body weight, and was the same for right and left kidneys as well as testes and bone. Whereas the position of the muscle (back, abdomen, hindlimb) and adipose tissue (perirenal and subcutaneous) had no influence on water content, for skin, a slight difference was found between back and abdomen. In general, the current results are in agreement with composite literature values, but provide in one study data for all tissues used in the development of physiologically based pharmacokinetic models of rat.

Animals↗
PubMed1997

Pharmacokinetics and tissue distribution of cisplatin and conjugates of cisplatin with carboxymethyldextran and A5B7 monoclonal antibody in CD1 mice.

The plasma disposition kinetics and tissue distribution of platinum was evaluated following intravenous bolus administration to CD1 immune-competent mice of cisplatin, cisplatin conjugated to anti-CEA monoclonal antibody A5B7 via a carboxymethyl dextran (CMdextran) carrier molecule, and cisplatin coupled to the CMdextran in the absence of antibody. In addition, the in vivo characteristics of 125I-labeled A5B7 were compared with and without conjugation to CMdextran. Conjugation of cisplatin [clearance (CL = 0.62 mL/min/g, volume of distribution at steady-state (Vdss) = 16 mL/g] to CMdextran restricted its tissue distribution (Vdss = 0.43 mL/g) and reduced its systemic clearance (CL = 0.055 mL/min/g). Subsequent conjugation of the complex to A5B7 further reduced both its distribution (Vdss = 0.20 mL/g) and clearance (CL = 0.016 mL/min/g). Clearance of A5B7 (CL = 0.002 mL/min/g) was increased by conjugation to CMdextran (CL = 0.014 mL/min/g); tissue distribution was unchanged. A5B7-CMdextran-cisplatin was relatively stable in plasma and other tissues, except the liver. The extent of distribution of platinum into tissues (lung, liver, muscle, kidney) was markedly influenced by conjugation, with the influence being greatest for unmodified cisplatin and least for the A5B7-CMdextran conjugate. However, the time courses of tissue distribution, expressed in mean residence time scales, were similar, implying a common mechanism controlling tissue uptake.

Animals↗
PubMed1997

Effect of altered tissue binding on the disposition of barbital in the isolated perfused rat liver: application of the axial dispersion model.

To examine the dependence of hepatic dispersion on tissue binding, the distribution kinetics of barbital under varying conditions of barbiturate perfusate concentrations was studied in the isolated perfused rat liver preparation (n = 5). The in situ liver was perfused in a single-pass mode with protein-free Krebs bicarbonate medium (15 mL/min). During steady-state infusion with various barbiturate concentrations (barbital, 1 g/L; butethal, 0.1, 1 g/L), a bolus containing [3H]water (cellular space marker) and [14C]barbital was injected into the portal vein. The recoveries of [3H]water and [14C]barbital were complete. The mean transit time and hence the volume of distribution for barbital in the absence of bulk barbiturate concentration (56 s and 1.24 mL/g) were about 2-fold higher than those for water (29 s and 0.58 mL/g), and they decreased progressively as the perfusate barbiturate concentration increased, indicating a decrease in tissue binding. However, the relative dispersion values (CV2H) of water (0.60) and barbital (0.66) were about the same magnitude and independent of the bulk concentration of barbiturate. The one-compartment dispersion model adequately described the data of barbital with a constant DN (dispersion number) value of 0.35. The results indicate that varying the tissue binding of barbital does not change the magnitude of DN; as such it offers a new experimental approach to examine the hepatic dispersion of solutes with a large distribution volume.

Animals↗
PubMed1997

Influence of morphometric factors on quantitation of paracellular permeability of intestinal epithelia in vitro.

PURPOSE: The relative contribution of the small and large intestine to paracellular absorption is a subject of some controversy. Direct comparison of paracellular permeability in different epithelia is complicated by variations in junctional density and/or the absorptive surface area. METHODS: This study used a combination of morphometric analyses and in vitro absorption studies to define permeability characteristics in relation to the amount of paracellular pathway present in rat ileum, colon and the model epithelium, Caco-2. RESULTS: Mucosal to serosal amplification was higher in ileum (3.9) than colon (1.9) or Caco-2 (1). Tight junctional density (lp) of ileal crypts was approximately 3 fold greater (91 m/cm2) than that measured in ileal villi, colonic surface and crypt cells or Caco-2 monolayers (34-37 m/cm2). However, when the relative contributions of the crypts and villi was taken into account there was no significant difference in the mean lp per mucosal area for the three epithelia studied. Using these data to correct for morphometric differences the permeabilities of a range of small hydrophilic molecules (atenolol, D-PheAsp and PEG oligomers MW 282-634) was measured. Permeability of rat ileum and colon were virtually identical for all compounds studied. In contrast, Caco-2 monolayers showed a significantly lower permeability than intestinal tissues with the difference increasing markedly with molecular size. CONCLUSIONS: These studies suggest the importance of accounting for morphological variation when comparing the permeability characteristics of different epithelial systems.

Animals↗
PubMed1997

Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat: a sensitivity analysis.

Sensitivity analysis studies the effects of the inherent variability and uncertainty in model parameters on the model outputs and may be a useful tool at all stages of the pharmacokinetic modeling process. The present study examined the sensitivity of a whole-body physiologically based pharmacokinetic (PBPK) model for the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) after i.v. bolus administration to rats. The aims were to obtain new insights into the model used, to rank the model parameters involved according to their impact on the model outputs and to study the changes in the sensitivity induced by the increase in the lipophilicity of the homologues on ascending the series. Two approaches for sensitivity analysis have been implemented. The first, based on the Matrix Perturbation Theory, uses a sensitivity index defined as the normalized sensitivity of the 2-norm of the model compartmental matrix to perturbations in its entries. The second approach uses the traditional definition of the normalized sensitivity function as the relative change in a model state (a tissue concentration) corresponding to a relative change in a model parameter. Autosensitivity has been defined as sensitivity of a state to any of its parameters; cross-sensitivity as the sensitivity of a state to any other states' parameters. Using the two approaches, the sensitivity of representative tissue concentrations (lung, liver, kidney, stomach, gut, adipose, heart, and brain) to the following model parameters: tissue-to-unbound plasma partition coefficients, tissue blood flows, unbound renal and intrinsic hepatic clearance, permeability surface area product of the brain, have been analyzed. Both the tissues and the parameters were ranked according to their sensitivity and impact. The following general conclusions were drawn: (i) the overall sensitivity of the system to all parameters involved is small due to the weak connectivity of the system structure; (ii) the time course of both the auto- and cross-sensitivity functions for all tissues depends on the dynamics of the tissues themselves, e.g., the higher the perfusion of a tissue, the higher are both its cross-sensitivity to other tissues' parameters and the cross-sensitivities of other tissues to its parameters; and (iii) with a few exceptions, there is not a marked influence of the lipophilicity of the homologues on either the pattern or the values of the sensitivity functions. The estimates of the sensitivity and the subsequent tissue and parameter rankings may be extended to other drugs, sharing the same common structure of the whole body PBPK model, and having similar model parameters. Results show also that the computationally simple Matrix Perturbation Analysis should be used only when an initial idea about the sensitivity of a system is required. If comprehensive information regarding the sensitivity is needed, the numerically expensive Direct Sensitivity Analysis should be used.

Animals↗
PubMed1997

Quantitative structure-pharmacokinetics relationships: I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat.

As part of an overall program to develop a framework for evaluating the contribution of structural and physicochemical properties to pharmacokinetics, the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) was examined after i.v. bolus administration in rats. The barbituric acids studied form a true homologous series; therefore any differences in pharmacokinetics, noted between congeners, can be directly linked to the increase in lipophilicity, resulting from the addition of a methylene group. A whole-body physiologically based pharmacokinetic model has been developed, assuming most of the tissues to be well-stirred compartments. Brain and testes, in which distribution for the lower homologues was permeability rate-limited, were represented by two compartments. For each homologue, the model parameters have been optimized, using the tissue concentration-time data. The initial distribution processes in the system were very rapid, making it quite stiff, and essentially over before the first samples were taken. A progressively increasing redistribution from lean tissues into adipose on ascending the homologous series was observed, characterized by a tendency for a progressive decrease in the magnitude of the concentration-time profiles for some of the lean and well-perfused tissues, an increase in the adipose concentration-time profile, and an increase in the time to reach the maximum adipose concentration. A shift from permeability rate limitation to perfusion rate limitation of the distribution processes for brain and testes, as well as an increase in the intrinsic hepatic clearance and decrease in the renal clearance with the increase of lipophilicity of the homologues, were quantified. An increase in the total unbound volume of distribution on ascending the homologous series was also observed. Muscle was found to be the major drug depot at steady state, accounting for approximately 50% of the total unbound volume of distribution, regardless of the lipophilicity of the homologue; the unbound volume of distribution of adipose increases more than 10-fold with the increase of lipophilicity.

Adipose Tissue↗
PubMed1997

A physiologically based pharmacokinetic model incorporating dispersion principles to describe solute distribution in the perfused rat hindlimb preparation.

A physiologically based pharmacokinetic model incorporating dispersion principles has been developed to describe outflow data from the isolated perfused rat hindlimb preparation, for the three reference markers 14C-sucrose, 14C-urea, and 3H-water and three 14C-labeled 5-n-alkyl-5-ethyl barbiturates; the methyl, butyl, and nonyl homologues. Also 51Cr-RBC and 125I-albumin were studied. The model consists of four parallel components representing each of the tissues comprising the hindlimb: skeletal muscle, skin, bone, and adipose. Attempts to simplify the model by using the principle of tissue lumping were made by examining the tissue equilibration rate constant k tau for each of respective tissues for each compound. It was found that simplification was only possible in the case of 3H-water data. The model took into account a possible shunting component in the skin tissue and incomplete mass but not volumetric recovery from the system. The dispersion model characterizes the relative spreading of solute on transit through a tissue bed by a dimension-less parameter DN. The estimated dispersion numbers (DN) obtained were in the region of 2.7-4.72, 8.39-15.54, 0.61-2.74, and 6.02-14.0 for skeletal muscle, skin, bone, and adipose, respectively, and were independent of the compound studied. These values are much larger than the range reported in the literature for hepatic outflow data, DN = 0.2-0.5, and suggest a greater heterogeneity of vascular flow in the different component tissues of the rat hindlimb.

Albumins↗
PubMed1997

Resistance of falciparum malaria to chloroquine and sulfadoxine-pyrimethamine in Afghan refugee settlements in western Pakistan: surveys by the general health services using a simplified in vivo test.

Surveys of drug resistant falciparum malaria were conducted in several Afghan refugee settlements, distributed over a 700 km range in western Pakistan, during the transmission seasons of 1994 and 1995. Symptomatic malaria patients were recruited by a process of passive case detection at the refugees' basic health units. To facilitate follow-up by local health workers, a modified version of the WHO extended in vivo test was adopted in which blood smears were taken from each subject, and clinical symptoms recorded, at weekly intervals. Resistance to chloroquine and sulfadoxine-pyrimethamine was identified in every settlement. The frequency of chloroquine resistance ranged from 18% to 62%. Resistance occurred mostly as RI, with RII resistance never exceeding 11%. Resistance to sulfadoxine-pyrimethamine occurred at much lower frequencies, ranging from 4% to 25%. There was a resumption of clinical symptoms at the onset of parasite recrudescence in over 90% of cases. The policy of using chloroquine as first-line treatment might be changed in favour of sulfadoxine-pyrimethamine in most camps and areas of western Pakistan. The modified in vivo test was almost as accurate as the normal WHO in vivo test in identifying the grade of resistance, and should prove a useful tool for the monitoring of resistance to common antimalarials by district health services.

Adolescent↗
PubMed1997

Chloroquine resistance in Pakistan and the upsurge of falciparum malaria in Pakistani and Afghan refugee populations.

Surveys conducted in Pakistan during the last decade show that falciparum malaria has become resistant to chloroquine in Pakistani and Afghan refugee populations throughout the country. Although RI resistance is common everywhere (with a frequency of 30%-84%), RII is rarer (2%-36%), and RIII resistance has yet to be detected. The national policy is to prescribe chloroquine as first-line treatment of malaria. A repeated in-vivo survey in a sentinel village indicated that prescription of chloroquine can lead to a 15% increase in the frequency of resistance in a single year, and similar trends were observed in other districts. Coinciding with the spread of resistance is a 6-fold increase in the number of falciparum cases recorded nationally between 1982 and 1992 and a parallel, 5-fold increase in the number of cases recorded in the Afghan refugee population. Resistance contributes to this trend in various ways. Firstly, patients with resistant malaria make repeated visits to health centres. In the sentinel village, for example, where resistance was measured at 71%, recrudescent infections inflated by 66% the genuine incidence of new infections recorded at the health centre. Secondly, owing to ineffective treatment, resistant infections are often still patent during the post-transmission season. This may enlarge the 'overwintering' parasite reservoir, leading to a surge of new cases when transmission resumes. Other factors potentially contributing to the upsurge in falciparum include the decrease availability of insecticide for indoor spraying. Despite the problems posed by resistance for case management, the evidence from the vector-control programme among the refugees is that malaria control through well-targeted campaigns of insecticide spraying is still able to reduce the incidence of falciparum malaria to a level that existed before the advent of resistance.

Afghanistan↗
PubMed1997

Pharmacokinetic perspectives on megadoses of ascorbic acid.

Ascorbic acid (vitamin C) is commonly used as a dietary supplement, often in megadoses. However, as the daily oral dose is increased, the concentration of ascorbic acid in the plasma and other body fluids does not increase proportionally, but instead tends to approach an upper limit. For example, when the daily dose is increased from 200 to 2500 mg (from 1.1 to 14.2 mmol) the mean steady state plasma concentration increases only from approximately 12 to 15 mg/L (from 68.1 to 85.2 mumol/L). Published data were reanalyzed with an integrated modeling approach to shed new quantitative light on this phenomenon. This analysis is based on the renal clearance of ascorbic acid, which rises sharply with increasing plasma concentrations as a result of saturable tubular reabsorption. The analysis indicates that both saturable gastrointestinal absorption and nonlinear renal clearance act additively to produce the ceiling effect in plasma concentrations. As a consequence of this ceiling effect, there is no pharmacokinetic justification for the use of megadoses of ascorbic acid.

Administration, Oral↗
PubMed1997

One week treatment for Helicobacter pylori infection.

Helicobacter pylori is associated with primary antral gastritis, duodenal ulceration, and gastric cancer. Current regimens for treating infection in children using bismuth and antibiotics for two to six weeks are cumbersome. The aim of this study was to evaluate a one week course of treatment. All children undergoing endoscopy were assessed for the presence of H pylori by culture, histology, rapid urease test, and 13C urea breath test. Infected children received a one week course of colloidal bismuth subcitrate 480 mg/1.73 m2/day (maximum 120 mg four times a day), combined with metronidazole 20 mg/kg/day (maximum 200 mg three times a day), and clarithromycin 15 mg/kg/day (maximum 250 mg twice a day). To optimise compliance, drugs were dispensed in a 'Redidose' box containing a compartment for each day, and subcompartments marked 'breakfast', 'lunch', 'dinner', and 'bedtime'. Compliance and side effects were assessed immediately after treatment. A urea breath test was performed at least one month after treatment. Twenty two children infected with H pylori were entered into the study; 20 of these took all doses; two children suffered significant side effects (diarrhoea and vomiting). H pylori was eradicated in 21 of the 22 children (95.45%; 95% confidence interval 77% to 100%). This study shows that H pylori infection in children can be cleared by a one week course of treatment.

Adolescent↗