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Biomedical subjects

M Rowland

Publications and source records attributed to M Rowland.

At least 91 records · Page 5Linked to original sources
PubMed1997

Sustainability of pyrethroid-impregnated bednets for malaria control in Afghan communities.

Between 1992 and 1995 a series of studies was undertaken to assess the long-term suitability of pyrethroid-impregnated bednets (PIBs) for malaria control in Afghan refugee communities in two villages in North-West Frontier Province, Pakistan. During 1992, 86% of bednet owners volunteered to have their bednets re-impregnated, and a further 15% of families purchased nets at two-thirds of cost price. From 1992 onwards, 27% of the villagers returned to Afghanistan, and annual house spraying campaigns were introduced to protect those still resident but sleeping without bednets. Within 3 years, these campaigns, together with PIBs, reduced the annual incidence of malaria by 87%, from 597 to 78 cases per 1000 population. Nevertheless, 65% of resident families continued to re-impregnate their nets annually with permethrin. To assess whether PIBs were still being used and were still protective, in view of these reduced transmission rates, we carried out a case--control study in 1994 on febrile or otherwise symptomatic patients presenting at village health centres. Comparison of the slide-positivity rates of PIB users and those without bednets showed that regular usage reduced the odds of contracting falciparum and vivax malaria to 0.22 (95% confidence interval (CI): 0.09-0.55) and 0.31 (95% CI: 0.19-0.51), respectively. There was no evidence of a sex- or age-bias in bednet use or in protective effect. The results indicate that a community-based PIB programme is an appropriate malaria control measure in areas where management or security problems make traditional house-spraying campaigns impossible. A relevant finding for those involved in the monitoring of bednet distribution projects is that the local coverage of bednets and the local impact on malaria, even when introduced to remote areas, can be estimated very cheaply by health centre microscopists who simply catalogue blood film diagnoses according to patients' bednet use practices.

Afghanistan↗
PubMed1996

Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies.

An expert meeting to discuss issues relating to the design of population pharmacokinetic/pharmacodynamic (PK/PD) studies was held in Brussels in March 1995, under the auspices of the European Co-operation in Science and Technology (COST), Medicine (B1) programme. The purpose of the meeting was to discuss the experts' experience in designing and performing population PK/PD studies. The topics discussed were current practice, logistical issues, ensuring the accuracy of data, covariate assessment, communication, and protocol design.

Belgium↗
PubMed1996

Pharmacokinetic considerations of regional administration and drug targeting: influence of site of input in target tissue and flux of binding protein.

Hunt et al. introduced the concept of the Drug Targeting Index (DTI) to quantify the gain associated with regional drug administration and targeting and showed that for the ideal case of all drug first reaching the target DTI = l + CLs/(QT(l-ET)) where CL, is the total clearance of drug from the body (including the target tissue). QT is the target blood flow and ET is the steady-state extraction ratio of the drug in the target. In the model they portrayed the tissue as a homogeneous organ. A more general pharmacokinetic model has been developed that takes into account the three anatomical spaces (vascular, interstitial, and intracellular) of the target organ or tissue and that, in addition to unbound drug permeating the vascular and cellular membranes, protein-bound drug can also flux between the vascular and interstitial spaces. Elimination of unbound drug can take place from the cellular and interstitial spaces. An important parameter influencing the DTI is shown to be the fraction of targeted dose that is eliminated there before it reaches the systemic circulation, fT. Equations have been developed showing the relationship between fT and ET and for DTI when drug is administered at the various sites within the tissue and under a variety of conditions. Only when drug is administered into the target arterial blood stream or when distribution of drug within the target tissue is perfusion rate-limited, does fT = ET and DTI = 1 + CLs/x (QT (I - ET)). Otherwise consideration needs to be given to the permeabilities of both the unbound and bound drug and site of target administration, interstitial or intracellular. Then fT is greater than ET and DTI is greater than that expected had perfusion-rate limited distribution prevailed. The maximum benefit in DTI is seen for a drug of low cellular permeability but high cellular intrinsic clearance administered intracellularly.

Drug Delivery Systems↗
PubMed1996

Comparison of HT29-18-C1 and Caco-2 cell lines as models for studying intestinal paracellular drug absorption.

PURPOSE: To compare the permeability characteristics of HT29-18-C1 colonic epithelial cell line with Caco-2, an established model of intestinal drug transport. METHODS: Cell lines were grown as epithelial monolayers. Permeability was measured over a range of transepithelial electrical resistance (Rt) using a group of drug compounds. RESULTS: HT29-18-C1 develop Rt slowly when grown in culture, allowing permeability to be measured over a wide range (80-600 Omega x cm2). In contrast, Caco-2 monolayers rapidly develop Rt of approximately equal 300 Omega x cm2 and require Ca2+ -chelation to generate Rt equivalent to human intestine (60-120 Omega x cm2). Permeability of atenolol, ranitidine, cimetidine, hydrochlorothiazide and mannitol across HT29-18-C1 decreased 4-5 fold as Rt developed from 100-300 Omega x cm2 indicating they permeate via the paracellular route. In contrast, ondansetron showed no difference in permeability with changing Rt consistent with transcellular permeation. Permeability profiles across low Rt HT29-18C1 and pulse EGTA-treated Caco-2 monolayers were the same for all 5 paracellular drugs suggesting that transient Ca2+ removal does not alter selectivity of the tight junctions. Permeabilities of cimetidine, hydrochlorothiazide and atenolol across 100 Omega x cm2 HT29-18-C1 monolayers reflect more closely those reported for the human ileum in vivo than did mature Caco-2 monolayers. CONCLUSIONS: HT29-18-C1 monolayers can be used to study drug permeability at Rt values similar to human intestine without the need for Ca2+ chelation. As such, they offer a useful alternative to Caco-2 for modelling intestinal drug absorption.

Atenolol↗
PubMed1996

Oral absorption of D-oligopeptides in rats via the paracellular route.

PURPOSE: This study was undertaken to examine the structural determinants of oral bioavailability in the rat of a set of oligopeptides comprising D-amino acids, which were taken to be absorbed paracellularly based on a pronounced sensitivity of permeability to electrical resistance in Caco-2 cell monolayers. METHODS: The study series comprised eleven D-oligopeptides, designed not to be recognised by peptidases or transport proteins, and to have molecular weights between 222 and 406 daltons with different net electrical charges and composition of D-amino acids. All the peptides were [3H]-radiolabelled and analyzed by HPLC with radiometric detection. Bioavailability was estimated based on 24-hr urinary excretion of unchanged peptide after oral and intravenous administrations. RESULTS: As expected, the series proved metabolically stable. Bioavailability was independent of oral dose when varied by a factor of 10,000, suggesting passive absorption. Whereas bioavailability decreased sharply from 30% to 1% with increasing molecular weight, net charge showed little, if any, effect on bioavailability. CONCLUSIONS: This D-oligopeptide model series served as a useful probe for the structural requirements for paracellular absorption in vivo. A critical determinant of bioavailability is molecular size, expressed as molecular weight in this study; net charged appeared of much lesser importance.

Absorption↗
PubMed1996

The use of population pharmacokinetics in drug development.

Currently, there is an increasing focus on the implementation of pharmacokinetic-pharmacodynamic (PK-PD) studies and modelling as essential tools for drug development. Strategies involving specifically the population approach, which are based on relatively recent statistical methodology (e.g. nonlinear mixed effects modelling, NONMEM) have been advocated for investigating pharmacokinetic and pharmacodynamic variability as well as dose-concentration-effect relationships. The present article outlines this approach, and discusses how it can be implemented within the framework of the studies currently performed as part of the clinical phases of new drug development. It also considers study design and performance, based on real-life experiences. Population approaches, if designed carefully and early, as part of the planning of the drug development programme, are expected to play a significant role at every phase of the programme and to contribute to providing information that is valuable for registration purposes. Statistical methodology and software are now widely available. However, practical issues such as integration of the population approach within existing protocols, quality control of the data, timing of laboratory and statistical analyses, as well as resource allocation, remain legitimate concerns to be considered in prospective studies.

Clinical Trials, Phase I as Topic↗
PubMed1996

Is the incidence of hemorrhagic stress ulceration in surgical critically ill patients affected by modern antacid prophylaxis?

Hemorrhagic stress ulceration (HSU), a known complication in the Surgical Intensive Care Unit (SICU) patient population, has a reported incidence rate of 25 to 75 per cent. The goal of this study was to evaluate whether the use of prophylactic antacid agents significantly reduced the frequency of HSU in critically ill patients, or whether improved care reflected the decrease in HSU. A total of 425 consecutive patients were reviewed for occurrence of HSU; of these, 304 were eligible for the study. Admitting diagnoses were trauma including head injury, postoperative patients, and patients with surgical complications. Inclusion criteria were length of stay in the SICU for at least 48 hours; antral gastric pH subsequently measured every 6 to 8 hours and maintained at > or = 4; and absence of the history of peptic ulcer disease or gastrointestinal bleeding. One group included 251 (83%) patients who were started on prophylactic agents (H2 blockers with or without antacids); the second group of 53 (17%) patients had no prophylaxis. The Injury Severity Score on admission to the SICU was 27.5 +/- 7.5, Apache II score was 26.4 +/- 6.4, and Revised Trauma Score was 4.3 +/- 2.3, with no difference in severity (P < 0.05). Thirteen (4%) patients were found to have evidence of HSU: 11 of 251 (4%) in the first group and 2 of 53 (4%) in the second. No statistically significant difference was found in the incidence of HSU between the two groups (P = 0.86). Results of this study suggest that modern prophylaxis for HSU did not significantly alter the incidence of stress ulceration in SICU patients.

Adolescent↗
PubMed1995

Discrepancies in pharmacokinetic parameter estimation between bolus and infusion studies in the perfused rat hindlimb.

Isolated, perfused rat hindlimb consists of skeletal muscle, skin, bone, and adipose. Hence, it is a heterogeneous preparation composed of slowly equilibrating tissues of different characteristics and fractional flow rates. This paper shows how caution should be exercised in interpreting the results following bolus administration and subsequent statistical moment analysis of intravascular markers (51Cr-erythrocytes and 125I-albumin) and lipophilic barbiturates. For the intravascular markers, the events in the hindlimb are overshadowed by events in the connecting tubing and cannulas, due to their comparable volumes. For the barbiturates, these estimates appear to apply to short-term effects as the volume estimates obtained following infusion to steady state are greater than after bolus administration. For the extravascular markers, 14C-sucrose, 14C-urea, and 3H-water, no such time dependency was shown. However, it is only from the outflow profiles following bolus administration that events in the tissue beds can be elucidated.

Animals↗
PubMed1995

Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine.

The low and variable bioavailability of cyclosporine has been attributed to poor absorption. However, recent studies have suggested that intestinal first-pass metabolism exerts a significant effect on bioavailability. We describe theory and methods to differentiate the contribution from oral absorption and intestinal and hepatic metabolism to overall cyclosporine bioavailability. Analysis of data from previous studies in our laboratories shows that in the absence of intestinal metabolism, cyclosporine absorption from its presently available dosage form averages at least 65% +/- 12% in healthy volunteers and 77% +/- 19% in kidney transplant patients. Analysis also suggests that the extraction ratio for cyclosporine in the gut is approximately twice the hepatic extraction and that cyclosporine absorption does not present a problem, with an average of 86% of the drug absorbed intact from its commercially available product in healthy volunteers. The boundary condition analysis described should have broad application in the differentiation of factors responsible for poor bioavailability.

Administration, Oral↗
PubMed1995

Comprehensive pharmacokinetics of urinary human follicle stimulating hormone in healthy female volunteers.

PURPOSE: The study determined the pharmacokinetics of urinary human follicle stimulating hormone (u-hFSH) in 12 down-regulated healthy female volunteers. METHODS: Following pituitary desensitization, baseline FSH serum levels were measured over a 24-hour period. Then each subject received, in random order, single doses of u-hFSH (Metrodin), 75 IU, 150 IU and 300 IU iv, and 150 IU im on four occasions separated by washout periods of one week. Blood and urine samples were collected at preset times. FSH levels were measured by a immuno-radiometric assay and an in vitro rat granulosa cells aromatase bioassay. RESULTS: All doses of u-hFSH were well tolerated. After an iv bolus, the pharmacokinetics of FSH were well described by a two-compartment open model. Immunoassay data showed that the total exposure to FSH was proportional to the administered dose. Mean total clearance of FSH was approximately 0.5 L.h-1 and renal clearance was 0.14 L.h-1. The volume of distribution at steady-state was around 8 liters. The distribution half-life was 2 h and the terminal half-life nearly one day. After im injection, almost two thirds of the administered dose was available systemically. The in vitro bioassay confirmed this pharmacokinetic analysis. CONCLUSIONS: The estimation of the elimination half-life of around one day indicates that the maximal effect of a given dose of u-hFSH administered daily cannot be observed until 3 to 4 days of repeated administration. This indicates that, on a pure pharmacokinetic basis, physicians should wait at least 4 days to assess the efficacy of a given dose of u-hFSH and that they should not modify dosage too frequently.

Adult↗
PubMed1995

Regional drug delivery II: relationship between drug targeting index and pharmacokinetic parameters for three non-steroidal anti-inflammatory drugs using the rat air pouch model of inflammation.

PURPOSE: To quantify the advantage gained by direct administration to a target site for two non-steroidal anti-inflammatory drugs (NSAIDs) piroxicam and diclofenac in the rat air pouch model of inflammation. To derive a model relating drug targeting index (DTI) to the pharmacokinetic parameters of the target and systemic sites, and to compare predictions with observations. METHODS: DTI was calculated based on area under the concentration time curve at target (pouch) and systemic site (venous blood) following administration into and sampling from both sites. A model was derived relating DTI to systemic clearance, target permeability, plasma protein binding and fraction of the targeted dose that is systemically available. RESULTS: Both NSAIDs exhibited linear pharmacokinetics over the dose ranges studies. They differed primarily in total body clearance which was approximately 16 fold greater for diclofenac (213 ml hr-1 per 250 g) than piroxicam (13 ml hr-1 per 250 g). Observed DTIs (11, 114 and 276 for piroxicam, S[+]ibuprofen [studied previously] and diclofenac) were ranked in order of total body clearance but were approximately 7.5 fold lower than predicted (101, 700 and 2214 respectively). CONCLUSIONS: The discrepancy was explained by the influx of the plasma binding protein, albumin, into the target site due to increased vascular permeability associated with the inflammatory response. The originally derived equation for DTI, which assumed only unbound drug diffuses across the target site, was modified to take into account the simultaneous flux of bound drug.

Animals↗
PubMed1995

Regional drug delivery I: permeability characteristics of the rat 6-day-old air pouch model of inflammation.

PURPOSE: To determine the permeability characteristics of the rat air pouch model of inflammation using permeability extremes within which the NSAIDs S[+] ibuprofen, piroxicam and diclofenac could be evaluated. METHODS: Permeability was calculated using concentration data obtained following intrapouch and intravenous administration of [3H]-water, [14C]-urea, [14C]-inulin and [125I]-albumin and compared to similar data obtained for the three NSAIDs. RESULTS: Similar permeability values (5-6.5 ml hr-1) were obtained for the three NSAIDS which fell between the permeability extremes of the molecular weight markers [3H]-water (9.7 ml hr-1), [14C]-urea (6.8 ml hr-1), [14C]-inulin (1.0 ml hr-1) and [125I]-albumin (0.6 ml hr-1). Coadministration of equipotent anti-inflammatory doses of the NSAIDs did not affect local blood flow to the air pouch (as assessed by urea kinetics) but did reduced vascular permeability (as assessed by albumin flux into the pouch). CONCLUSIONS: Comparison of the NSAIDs with the permeabilities of the molecular weight markers indicates that a perfusion rate limitation probably exists. Systemic absorption is complete over the first two hours following intrapouch administration of the NSAIDs, therefore albumin flux into the pouch is insufficient to materially affect the permeability of the NSAIDs. However, subsequently (post 5hr) albumin concentration in the pouch rises sufficiently to lower the effective flux of the NSAIDs.

Animals↗
PubMed1995

Helicobacter pylori infection and peptic ulcer disease in children.

Peptic ulcer disease is an uncommon disorder in children. The recent upsurge of interest in peptic ulcer disease in children can be attributed to the importance of studies of children in establishing the role of Helicobacter pylori in the pathogenesis of ulcer disease. This review of recent publications focuses on the role of the organism in peptic ulcer disease, the epidemiology of H. pylori, its significance as a cause of symptoms, and recent advances in the treatment of this infection. The increasing evidence that chronic H. pylori gastritis is possibly a significant risk factor for the development of gastric carcinoma is also discussed.

Breath Tests↗
PubMed1995

Pyrethroid-sprayed tents for malaria control: an entomological evaluation in Pakistan.

Field trials were undertaken in the North West Frontier Province of Pakistan to determine the effects of pyrethroid-sprayed tents on feeding success, mortality and biting-rates of wild mosquitoes attracted to bait cows confined within the tents. Under natural conditions, endophagic mosquitoes rested only briefly in untreated tents during the night, followed by complete exodus at dawn. In tents sprayed on the interior surface with permethrin 0.5 mg/m2 or with deltamethrin 0.03 g/m2 the biting rate of Anopheles stephensi was reduced by about 40%; deterrency against culicines and other anophelines was much less. Mortality-rates of bloodfed mosquitoes from the treated tents were 75% An.stephensi, 65% An.subpictus but only 10% of culicines. Outer fly-sheets prolonged the effective life of the treatment; bioassays on the sprayed inner-sheets showed that insecticidal efficacy remained high for over a year, whereas on tents without fly-sheets permethrin residual efficacy declined rapidly 20-40 weeks post-treatment. It is concluded that tent-spraying with fast-acting photostable residual pyrethroid insecticide would probably provide effective protection against malaria transmission for the inhabitants of tents in any part of the world where the vector mosquitoes are endophilic and susceptible to pyrethroids.

Animals↗
PubMed1995

Pharmacodynamic comparison of regional drug delivery for non-steroidal anti-inflammatory drugs, using the rat air-pouch model of inflammation.

The inhibition of prostaglandin E2 (PGE2) synthesis by S-(+)-ibuprofen and piroxicam have been assessed following intravenous and regional (intrapouch) drug delivery using the rat air-pouch model of inflammation. Anti-inflammatory response was defined as the decrease in the area under the exudate PGE2 concentration-time curve between 3 and 10 h, following regional administration of the irritant carrageenan. Dose-response studies indicated that bolus regional administration of S-(+)-ibuprofen increased potency 30-fold compared with systemic administration and could be further improved 10-fold by regional infusion, whereas regional administration of piroxicam showed no therapeutic advantage. Examination of the concentration-response using AUC revealed that for a given response, average pouch concentrations for S-(+)-ibuprofen during the PGE2 inflammatory response (3 to 10 h) was similar, irrespective of route or mode of administration. In contrast, an advantage following systemic rather than regional administration was revealed for piroxicam, based on plasma concentration-response data, indicating a major systemic anti-inflammatory component for piroxicam but not for S-(+)-ibuprofen. These observations stress the need to take account of both pharmacodynamics and pharmacokinetics when considering the potential advantage of regional administration.

Animals↗
PubMed1995

Membrane permeability and lipophilicity in the isolated perfused rat liver: 5-ethyl barbituric acid and other compounds.

The distribution kinetics of 5-ethyl barbituric acid (EBA) has been examined in the rat liver. The isolated in situ liver (n = 4) was perfused at a constant rate (15.1 +/- 0.2 ml/min, mean +/- S.D.) with protein-free Krebs bicarbonate medium in a single-pass mode. [14C]Sucrose (extracellular reference) and [14C]EBA were injected separately as bolus doses into the portal vein. The outflow data were analyzed using the axial dispersion model. The one-compartment dispersion model adequately described the data for sucrose, with a dispersion number (DN) of 0.25 +/- 0.04 and a volume of distribution (VH) of 0.14 +/- 0.01 ml/g liver. The two-compartment dispersion model, which incorporates a cellular permeability barrier, provided a better description of the EBA outflow data. The estimated VH, influx and efflux rate constants and permeability-surface area product (PS) for EBA were 0.37 +/- 0.04 ml/g liver, 0.028 +/- 0.004 sec-1, 0.019 +/- 0.001 sec-1 and 3.4 +/- 0.5 ml/min, respectively. Despite low hepatocyte membrane permeability, the DN value for EBA (0.28 +/- 0.03) was not significantly different from that of sucrose, which supports the concept that dispersion of compounds in the liver is primarily determined by the heterogeneity of the hepatic microvasculature. The relationship between PS values in the perfused rat liver (either abstracted or taken from the literature data) and physicochemical properties for 17 compounds has been explored. There appears to be a continuous relationship between PS and logD, a measure of lipophilicity that takes into account the degree of ionization in the perfusate. The PS value for EBA is close to that expected based on its physicochemical properties.

Animals↗