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Biomedical subjects

M Rowland

Publications and source records attributed to M Rowland.

At least 37 records · Page 2Linked to original sources
PubMed2001

Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers.

Despite significant advances in the characterization of tight junction (TJ) proteins, little is known about how molecular changes relate to function due primarily to the limitations of conventional paracellular probes. To address this, the paracellular pathway in Caco-2 and T84 cell lines was profiled by measuring the permeabilities of 24 polyethylene glycols (PEG) of increasing molecular radius (3.5--7.4 A) analyzed by mass spectrometry. When combined with a paracellular sieving model, these data provided quantitative descriptors of the pathway under control conditions and after exposure to TJ modulators. PEG profiles in both cell lines conformed to a biphasic process involving a restrictive pore (radius 4.3--4.5 A) and a nonrestrictive component responsible for permeability of larger molecules. PEG profiling revealed significant differences between the effects of EGTA and sodium caprate (C10). The restrictive component of EGTA-treated cells lost all size discrimination due to an increase in pore radius. Sodium caprate had no effect on pore radius but increased permeability via a different mechanism possibly involving increased numbers of functional pores. PEG profiling provides a useful tool for probing the functional regulation of the paracellular route.

Biomarkers↗
PubMed2001

Is Helicobacter pylori infection in childhood a risk factor for gastric cancer?

Helicobacter pylori infection is associated with chronic gastritis and peptic ulcer disease. Furthermore, the World Health Organization has classified this organism as a carcinogen for gastric cancer. H pylori infection is mainly acquired in childhood. Children with H pylori infection are asymptomatic except for a very small number that develop peptic ulcer disease. However, if H pylori gastritis is associated with gastric cancer, do pediatricians need to screen children for this infection and treat those who are infected? In an attempt to determine the significance of the association between H pylori and gastric cancer, we have reviewed all of the English language literature on this topic. H pylori infection seems to be associated with an increased risk of developing gastric cancer. However, only a small number of infected individuals (~1%) will develop gastric cancer. Furthermore, there are potential cofactors other than H pylori that could be equally important. The effect of the eradication of H pylori alone on the development of gastric cancer is unknown. Based on our knowledge to date, we suggest that it is not indicated to treat all children with H pylori infection because of the risk of developing gastric cancer or to institute a screening and treatment program.

Adenocarcinoma↗
PubMed2001

Intervention epidemiology training: a European perspective.

Within the widening European Union, large-scale movements of people, animals and food-products increasingly contribute to the potential for spread of communicable diseases. The EU was given a mandate for public health action only in 1992, under the Treaty of European Union ("Maastricht Treaty"), which was broadened in the 1997 with the Treaty of Amsterdam. While all EU countries have statutory requirements for notifying communicable diseases, national and regional communicable disease surveillance practices vary considerably. The Network Committee (NC) for the Epidemiological Surveillance and Control of Communicable Diseases in the EU was established in 1998 to harmonise these activities.

Academies and Institutes↗
PubMed2001

Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia.

Intestinal drug efflux mediated by P-glycoprotein and other ABC transporters is widely accepted as a reason for low or variable oral absorption. However, little is known about species and regional differences in P-glycoprotein so the functional and predictive relevance of observations made in cell models such as Caco-2 is uncertain. The aim of this study was to define the kinetics of drug efflux in rat and human intestinal tissues in vitro using the "reference" substrates digoxin and vinblastine. The expression and functional role of other ABC transporters in the transport of these compounds was also investigated. Saturable, verapamil-sensitive efflux of digoxin was observed in all intestinal regions. Apparent affinity of the efflux process varied within a relatively narrow range (50-92 microM), increasing in rat from small to large intestine. In contrast, maximal transporter activity varied over a 4- to 5-fold range with ileum > jejunum > colon. Similar regional differences in efflux were also observed with vinblastine. Maximal efflux levels were similar in Caco-2 and ileum for both substrates, suggesting that Caco-2 may quantitatively predict small intestinal drug efflux. Digoxin efflux kinetics was virtually identical in rat and human colon. Inhibitor studies showed that digoxin and vinblastine efflux in intestinal tissues was mediated by P-glycoprotein, although a minor component could be attributed to multidrug resistance-related protein (MRP)-like transporters in Caco-2. This study has analyzed the differential functional expression of drug efflux along the gastrointestinal tract. Such data will be critical in developing predictive models of P-glycoprotein-mediated efflux using information gathered from in vitro systems.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Uptake of teicoplanin by isolated rat hepatocytes: comparison with in vivo hepatic distribution.

Tissue distribution of teicoplanin, a large glycopeptide antibiotic, is slow but at equilibrium its whole body distribution volume is relatively large (Vss = 1.18-2.78 liter/kg), despite a high binding to plasma albumin. In vivo distribution into liver is extensive. Previous in vitro homogenate studies suggest that teicoplanin binds to cell membranes but only enters some cells. This possibility was investigated with isolated hepatocytes incubated for 4 h with [14C]teicoplanin alone and in the presence of additional teicoplanin (1 and 100 microg/ml). Uptake was determined after separating the cells by rapid centrifugation through a dibutyl phthalate layer and assessing viability by the trypan blue exclusion test. Teicoplanin cell uptake curves, initially rapid followed by slower distribution (which agrees with in vivo findings), were adequately described by a closed two-compartment model. Whereas entry into hepatocytes was independent of drug concentration, binding to the cell exterior membrane was concentration-dependent. The equilibrium distribution ratio (Kpu(c) +/- S.D.; 42 +/- 10) was somewhat smaller than estimated in vivo (106 +/- 9), but similar to that reported previously in vitro using liver homogenates (54 +/- 11). Also, the estimated membrane permeability-surface area product was larger in vitro than in vivo (PSu +/- S.D.; 5.5 +/- 2.9 versus 0.74 +/- 0.10 ml/min per whole liver). The most likely explanation for this difference is that in vivo only a small fraction of the total cell surface area is exposed to the perisinusoidal space, where exchange occurs.

Aminoglycosides↗
PubMed2001

Caffeine ingestion elevates plasma insulin response in humans during an oral glucose tolerance test.

We tested the hypothesis that caffeine ingestion results in an exaggerated response in blood glucose and (or) insulin during an oral glucose tolerance test (OGTT). Young, fit adult males (n = 18) underwent 2 OGTT. The subjects ingested caffeine (5 mg/kg) or placebo (double blind) and 1 h later ingested 75 g of dextrose. There were no differences between the fasted levels of serum insulin, C peptide, blood glucose, or lactate and there were no differences within or between trials in these measures prior to the OGTT. Following the OGTT, all of these parameters increased (P < or = 0.05) for the duration of the OGTT. Caffeine ingestion resulted in an increase (P < or = 0.05) in serum fatty acids, glycerol, and plasma epinephrine prior to the OGTT. During the OGTT, these parameters decreased to match those of the placebo trial. In the caffeine trial the serum insulin and C peptide concentrations were significantly greater (P < or = 0.001) than for placebo for the last 90 min of the OGTT and the area under the curve (AUC) for both measures were 60 and 37% greater (P < or = 0.001), respectively. This prolonged, increased elevation in insulin did not result in a lower blood glucose level; in fact, the AUC for blood glucose was 24% greater (P = 0.20) in the caffeine treatment group. The data support our hypothesis that caffeine ingestion results in a greater increase in insulin concentration during an OGTT. This, together with a trend towards a greater rather than a more modest response in blood glucose, suggests that caffeine ingestion may have resulted in insulin resistance.

Administration, Oral↗
PubMed2000

Estimation of aqueous distributional spaces in the dual perfused rat liver.

1. The aim of this study was to estimate the aqueous distributional spaces of the liver as a function of the route of input: portal vein (PV) versus hepatic artery (HA). 2. Studies were performed in the situ single (PV) and dual (PV-HA) perfused rat liver (n = 6-10) using Krebs bicarbonate buffer at constant PV (12 ml min-1) and HA (3 ml min-1) flow rates. An impulse input-output response technique was employed, varying the route of input, using non-labelled erythrocytes (intravascular marker), 125I-albumin and [14C]sucrose (extracellular markers), and [14C]urea and 3H2O (total water markers) as the reference indicators. 3. Distributional spaces were estimated using two different methods, namely standard and specific. The standard method was applied to hepatic outflow data obtained from the single PV perfused liver. The specific method was used when operating in the dual perfused mode to provide an estimate of the excess space perfused solely by the HA input. Specific spaces, interstitial and intracellular volumes, were estimated by difference. 4. The results were evaluated by means of visual inspection of the outflow profiles and comparison of the distributional spaces. Different hepatic effluent profiles obtained as a function of the route of input indicated that these two inputs did not completely mix within the liver. Estimates of the distributional spaces supported this observation, and further suggested that the arterial input perfuses 9-12 % more hepatic tissue than the venous input. 5. The knowledge obtained from the existence of a specific arterial space can be extended to help make predictions about the fate of an eliminated compound following arterial administration. Any difference between the HA and PV in terms of hepatic recovery could be attributed to this excess space and its enzyme density.

Animals↗
PubMed2000

Prediction of in vivo tissue distribution from in vitro data 1. Experiments with markers of aqueous spaces.

PURPOSE: The aim of this study was to evaluate the ability of an in vitro method of tissue distribution to accurately predict total water and extracellular aqueous spaces using marker compounds urea and inulin. METHODS: Slices (50-200 mg) of all the major tissues in the rat were incubated with Hanks/HEPES pH7.4 buffer containing 14C-urea and 3H-inulin for 2 h at 37 degrees C. Tissue weight was noted before and after incubation and the tissue-to-buffer ratios determined. RESULTS: 14C-Urea Kp estimates were generally greater than total tissue water due to tissue swelling, which varied widely among the tissues, up to 41% in muscle. In most cases, Kp values were much closer to in vivo values after correcting for the 14C-urea in the imbibed media (Kpcorr). The method was able to distinguish between 14C-urea and 3H-inulin Kp values and indicated that inulin occupied a smaller space than urea, which for the majority of tissues corresponded to the extracellular space. CONCLUSIONS: The Kp(corr) values for 14C-urea and Kp for 3H-inulin were consistent with total tissue water and extracellular space for the majority of tissues studied, indicating their suitability as marker compounds for checking the viability of this in vitro method for estimating tissue distribution.

Animals↗
PubMed2000

Indoor residual spraying with alphacypermethrin controls malaria in Pakistan: a community-randomized trial.

We conducted a community-randomized controlled trial in Pakistan to determine the efficacy of indoor residual spraying with alphacypermethrin ('Fendona', Cyanamid, NJ, USA), applied at 25 mg/m2, to prevent falciparum and vivax malaria. Wettable powder (WP) and suspension concentrate (SC) formulations were tested against an unsprayed control in an irrigated rice-growing area of Sheikhupura district, Punjab province. The study area of 180 km2 was divided into nine sectors, which were assigned at random to control, WP, or SC treatments in replicates of 3. Sentinel villages were selected from each sector for entomological and disease monitoring. Malaria was monitored by fortnightly active case detection (ACD) and by cross- sectional parasite surveys on schoolchildren. Mosquito populations were monitored by space spraying of rooms and by cattle-landing catches. The spray campaign took place in June 1997 and covered 96% of compounds. During the 7 months after spraying, the incidence of falciparum malaria was 95% lower and that of vivax malaria 80% lower in WP-sprayed than unsprayed sectors. Similar results were obtained for sectors sprayed with the SC formulation. Cross-sectional surveys gave estimates of efficacy comparable to those obtained by ACD. Anopheles culicifacies was 80% less abundant and A.stephensi, the predominant anopheline, was up to 68% less abundant in sprayed areas over the 7-month period. Reductions in anopheline parous rates indicated that the single-spray treatment was effective for the entire transmission season. Sprayed surfaces lacked odour, which contributed to the popularity of the campaign. Alphacypermethrin is a promising insecticide for the control of malaria in Pakistan and South Asia generally.

Animals↗
PubMed2000

Tolerance to ischemia and hypoxia is reduced in aged human myocardium.

BACKGROUND: Recovery of cardiac function after cardiac surgery and other interventional cardiac procedures in elderly patients is inferior to that in younger patients, suggesting that the aged myocardium is more sensitive to ischemia and other stresses. Although convincing data from animal studies of senescence now exist, there is a dearth of controlled in vitro studies that examine the specific response of aged human myocardium to the stress of hypoxia or ischemia. OBJECTIVE: We sought to determine the effect of age on the capacity of human atrial trabeculae to recover contractile function after in vitro hypoxic or ischemic stress. METHODS: Atrial pectinate trabeculae were dissected from the tip of 58 right atrial appendages harvested during an operation in patients aged between 34 and 89 years and electrically stimulated at 1 Hz in oxygenated Ringer's solution at 37 degrees C. Tissues experienced 30 minutes of either hypoxia (N(2) and perfusate) or simulated ischemia (humidified N(2) without perfusate) and were returned to normoxia for recovery of function for 30 minutes. Developed force and other contractile variables were determined during each period. RESULTS: Under normoxic conditions, no significant age difference was observed for any contractile function variable. However, after hypoxia, the old (70-89 years) and intermediate age groups (60-69 years) showed reduced recovery of developed force (48.5% +/- 22.2% [n = 11] and 44.9% +/- 19% [n = 12], respectively) compared with that found (66.4% +/- 19.7% [n = 15]) in the younger (34-59 years) group (mean +/- SD, P =.02). Similarly, after simulated ischemia, the groups of 70- to 89-year-old and 60- to 69-year-old subjects showed reduced recovery of developed force (35.7% +/- 17% [n = 5] and 51.1% +/- 11.8% [n = 9], respectively) compared with that found (68.2% +/- 10.4% [n = 6]) in the group of 34- to 59-year-old subjects (P =.01). Multivariable analysis, comparing 20 factors of surgical patient characteristics and recovery of developed force, found that only age (P =.01) and hypertension (P =.01) were predictors of reduced recovery of developed force after either hypoxia or simulated ischemia. CONCLUSIONS: In aged human atrial myocardium, the capacity to recover contractile function after in vitro hypoxia or simulated ischemia is reduced compared with the younger myocardium of mature adults. These findings suggest that enhanced myocardial protective strategies may be indicated for elderly patients undergoing cardiac surgery.

Adult↗
PubMed2000

Optimizing the science of drug development: opportunities for better candidate selection and accelerated evaluation in humans.

Two international meetings were convened in 1998 to review the current science of drug development and the potential opportunities to optimize the evaluation of new drugs in humans. This report represents a synopsis of these meetings, and focuses on the current state of knowledge pertaining to drug development, future scientific and technical needs, and the relative merits of various strategies intended to accelerate the clinical development of drugs.

Animals↗
PubMed2000

Dose-dependent pharmacokinetics of cyclosporin A in rats: events in tissues.

Cyclosporin A (CyA) tissue distribution kinetics was extensively studied after single 1.2-, 6-, and 30-mg/kg CyA doses (via 2-min i.v. infusion) to rats. Drug concentrations in blood and various tissues were measured using a specific radioimmunoassay. Based on total blood concentration data alone, CyA systemic pharmacokinetics appeared essentially linear. However, after taking the saturable, nonlinear blood cell binding into account, multiple nonlinear factors were identified. Intrinsic clearance at 30 mg/kg was about half the value at the two lower doses. Tissue distribution was also dose-dependent, with evidence of saturable binding in many tissues. In general, blood binding saturation (dissociation constant K(D) = 0. 18 microg/ml) occurred at a lower dose (concentration) than saturation of tissue binding (K(D), 0.005-0.77 microg/g), such that the volume of distribution at steady state first increased as the dose increased from 1.2 to 6 mg/kg, and then decreased as the dose increased to 30 mg/kg. Tissue binding was further investigated by various graphical analyses. Some organs showed a monophasic (single site) Scatchard plot of the tissue data at steady state, with high K(D) values. In other organs, biphasic binding characteristics were observed with the K(D) values of the high-affinity site in the same range as the K(D) reported for the binding of CyA with cyclophilin, the putative target. Saturable tissue binding may therefore influence not only the pharmacokinetics but also the efficacy of CyA.

Algorithms↗
PubMed2000

Evaluation of route of input on the hepatic disposition of diazepam.

Diazepam, a drug of high intrinsic clearance, was studied in the in situ rat liver dually perfused with Krebs-bicarbonate buffer containing human serum albumin (HSA; 0-1%) and unlabeled diazepam (1 mg/l) under constant hepatic arterial (3 ml/min) and portal venous (PV; 12 ml/min) flow rates. Events after a unit impulse (using [(14)C]diazepam) and at steady state (using unlabeled diazepam) were evaluated. In the absence of HSA the fractional effluent recovery (F) after hepatic arterial infusion (0.046 +/- 0.013) was about twice that after PV infusion (0.019 +/- 0.006). With HSA present, regardless of input route, F increased as unbound diazepam fraction in perfusate decreased (e.g., for PV, F = 0.58 +/- 0.05 and 0.69 +/- 0.02 for unbound diazepam fraction values of 0.18 +/- 0.01 and 0.037 +/- 0.01 at 0.25% and 1% HSA). The effluent [(14)C]diazepam profile was also dependent upon HSA. On decreasing HSA from 1 to 0.25% the early sharp peak (at 12-20 s) was replaced by a flatter unimodal profile with a later peak (at 60-80 s). Comparison of estimated effective permeability-surface area product to perfusate flow ratios (4.4 for 1% HSA and 21 for 0.25% HSA) indicated a shift from a perfusion rate-limited uptake with 0.25% HSA to one intermediate between permeability and perfusion at 1% HSA. Recognizing that orally absorbed drug enters the liver only via PV and i.v. drug via both vascular routes, this study emphasizes the difference in hepatic extraction of compounds depending on route of input, and the role that alteration in perfusate binding has on hepatic drug disposition.

Animals↗
PubMed1999

The effect of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin in humans.

OBJECTIVE: The interaction of multiple oral doses of cimetidine on the steady-state pharmacokinetics and pharmacodynamics of warfarin was investigated in six healthy male volunteers. METHODS: The subjects were given individually adjusted doses of warfarin to achieve therapeutic levels of prothrombin activity. The established daily maintenance oral dose of warfarin was kept stable throughout the trial and, on study days 8-14, each volunteer received a 800-mg daily dose of cimetidine. The degree of anticoagulant response produced by warfarin was quantified by the determination of both the prothrombin time and factor-VII clotting activity. RESULTS: Cimetidine co-administration had no significant effect on the pharmacokinetics of the more potent S-warfarin but significantly increased by 28% (P < 0.05) mean R-warfarin trough plasma concentrations and decreased by 23% (P < 0.05) mean R-warfarin apparent clearance. Both prothrombin time and factor-VII clotting activity displayed considerable inter-subject variability and were not significantly affected by concurrent cimetidine treatment. The reduction of apparent clearance of R-warfarin by cimetidine was found to be the effect of inhibition of the formation of warfarin metabolites as determined by apparent formation clearance values (+/-SD) of R-6-hydroxywarfarin (31.1+/-7.4 ml/h baseline; 18.5+/-4.5 ml/h at end of cimetidine treatment; P < 0.01), and R-7-hydroxywarfarin (6.9+/-1.3 ml/h baseline; 4.3+/-1.1 ml/h at end of cimetidine treatment; P < 0.01). CONCLUSION: Cimetidine stereoselectively affects the steady-state pharmacokinetics of warfarin by inhibiting the disposition of the less potent R-warfarin in humans. However, this interaction is likely to be of minimal clinical significance in most patients.

Adolescent↗