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Biomedical subjects

A G Harris

Publications and source records attributed to A G Harris.

138 records · Page 8Linked to original sources
PubMedDate not supplied

Ischemia and reperfusion in pancreas.

Ischemic diseases of heart and brain are the primary causes of mortality in industrialized nations. The ischemic injury with the consecutive reperfusion is responsible for the disturbance of microcirculation with ensuing tissue damage and organ dysfunction. Recent evidence suggests that oxygen-derived free radicals and activated polymorphonuclear leukocytes produced in ischemic tissue are instrumental in the development of ischemic cell injury. In pancreas, ischemia/ reperfusion is proposed as a potentially damaging factor accounting in part for the pathogenesis of acute pancreatitis. Apart from ischemia/reperfusion injury, the kallikrein-kinin system mediates acute inflammation associated with enhanced capillary permeability and accumulation of polymorphonuclear leukocytes, cardinal features of ischemia/reperfusion injury also in acute pancreatitis. Therefore, it seems reasonable to use bradykinin-antagonists to influence postischemic reperfusion injury of the pancreas. In the following, we describe the pathophysiology of ischemia/reperfusion injury with special reference to the pancreatic microcirculation and morphological changes as observed in a model of complete and reversible ischemia. Furthermore, we will discuss the effects of two bradykinin-antagonists (HOE 140 and CP-0597) on functional integrity of the pancreas after ischemia/ reperfusion.

Bradykinin↗
PubMedDate not supplied

Sustained reduction of exercise perfusion defect extent and severity with isosorbide mononitrate (Imdur) as demonstrated by means of technetium 99m sestamibi.

BACKGROUND: The impact of long-acting nitrates on the extent and severity of stress-induced myocardial ischemia is not well described, especially after long-term treatment. METHODS: Forty patients with chronic stable angina and reversible ischemia on an exercise stress myocardial perfusion single photon emission computed tomography (ex-SPECT) were prospectively studied in a 6-week period. At baseline, rest thallium-201/exercise stress technetium 99m sestamibi SPECT was performed, followed by treatment with extended-release isosorbide 5-mononitrate (5-ISMN, Imdur). Follow-up ex-SPECT was performed 5 days and 6 weeks after the initiation of therapy with extended-release 5-ISMN. The exercise treadmill testing (ETT) protocol and exercise duration of the follow-up studies were the same as that of the baseline ETT. Defect extent and severity were analyzed both by means of an automated quantitative method, with CEqual software, and visually, with a 20-segment scoring system (which was also used to derive a summed stress score [SSS]). RESULTS: In the 6-week study period, significant reductions occurred in both the extent and the severity of exercise-induced ischemia by means of quantitative SPECT (13.8% [P<.0003] and 12.7% [P<.0003], respectively). There was no significant change in these variables between stages 2 (day 5) and 3 (6 weeks), indicating no development of tolerance to the nitrate effect. Similar reductions were noted by means of the visual analysis (SSS reduction of 13.0% [P<.002]) in the entire study period. CONCLUSIONS: Patients with chronic-stable-angina treated with a long-acting nitrate demonstrate improvement in myocardial perfusion defect extent and severity in an extended period by means of both visual and quantitative analysis of sequential exercise testing to the same rate-pressure product end point.

Aged↗
PubMedDate not supplied

Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy. 1. General principles.

The safety of long-term inhaled corticosteroid therapy at commonly prescribed doses is an issue of growing concern to physicians and international regulatory bodies. This is so because long-term use of these drugs has become the mainstay of chronic asthma management and their introduction now is widely recommended in official treatment guidelines at the 'mild persistent' stage of asthma, where regular daily therapy is first begun. In addition to more frequent use of inhaled corticosteroids, there is a further trend to use higher doses of existing inhaler therapies and to use the newer and more potent compounds that have recently become available. At the same time as these developments have been taking place, there has not been a concurrent move to a more rigorous examination of the safety profile of these inhaled corticosteroid treatments - especially to assess their effects on the hypothalamic-pituitary-adrenal (HPA) axis. Most safety data with respect to HPA axis effects have been derived from testing methods that are limited in their ability to detect HPA system impairment and, more seriously, that can give the impression of functional integrity in the HPA axis when there may be moderate (or even greater) impairment. In this first part of a two-part review of the HPA axis effects of inhaled corticosteroids and of how these effects should be assessed, we examine the currently used and the currently available testing methodologies and also review the present state of knowledge concerning the structure and function of the HPA axis and the effects of its suppression. It is clear that there are state-of-the-art tests to assess in a discriminating manner the safety profile of inhaled corticosteroids. These tests have been insufficiently employed, including during the drug development process, yet they are readily available, relatively inexpensive and can detect adrenal suppression before the appearance of clinical effects. In part 2 of this review we examine what can be learned about the effects of inhaled corticosteroid therapy on the HPA axis from the limited amount of reliable published information from clinical and pharmacological studies describing their use and safety.

Administration, Inhalation↗
PubMedDate not supplied

Hypothalamic-pituitary-adrenal axis suppression and inhaled corticosteroid therapy. 2. Review of the literature.

In the first part of this two-part review it was noted that inhaled corticosteroids had become the mainstay of treatment for chronic asthma and yet the effects of long-term use of these compounds on the hypothalamic-adrenal-pituitary (HPA) axis were largely being determined by testing methods of limited reliability, especially by morning plasma cortisol measurements. It was established in our examination of the published literature and in our presentation of current knowledge of the structure and function of the HPA axis that safe, accurate and discriminating techniques to assess the functional status of the HPA axis were available. It was concluded that two state-of-the-art tests that have been insufficiently used were the ACTH stimulation test and measurement of the 24-hour integrated serial plasma cortisol concentrations. These two tests can detect adrenal suppression before the appearance of clinical effects. For part 2 of this review we conducted an exhaustive search of the English language clinical and pharmacological literature on the use of inhaled corticosteroids from 1988 until the present time to identify studies in which one or both of these testing methods have been used. We present our analysis of this limited number of studies to determine what accurately can be known of the HPA axis safety profile of three of the most commonly used and investigated inhaled corticosteroids - beclomethasone dipropionate, budesonide and fluticasone propionate. The first finding of significance was that only 50 reports were identified in which information on the HPA axis safety effects of orally inhaled steroids in asthma patients or in clinical pharmacological studies met our inclusion requirements. By analysis of the data presented in these reports we were able to reach the following conclusions: (1) inhaled corticosteroids administered chronically, and prudently, within recommended dose ranges do not endanger the functioning of the HPA axis, (2) the increasing tendency to use higher doses of inhaled corticosteroids on the assumption that there are clear dose-response benefits and no adverse HPA axis effects from long-term high-dose regimens is misguided and not supported by reliable published information, (3) the corollary - that higher corticosteroid potencies (as measured, for example, by skin-blanching activity) can have greater therapeutic effect in lung tissue without greater concomitant systemic activity - is a flawed concept, and (4) the limited clinical and pharmacological data support our part 1 conclusions that discriminating techniques to assess the functional HPA axis status should be an integral part of the drug development process and that further HPA axis function studies are required on existing inhaled corticosteroids - if they lack a rigorous testing history or long-term record of clinical safety.

Adrenal Cortex Hormones↗
PubMedDate not supplied

The Cytoscan Model E-II, a new reflectance microscope for intravital microscopy: comparison with the standard fluorescence method.

The Cytoscan Model E-II (Cytometrics Inc., Philadelphia, Pa., USA) is a newly developed instrument which functions as an intravital microscope and is small and easily portable. Through the use of orthogonal polarization spectral (OPS) imaging, the Cytoscan Model E-II delivers images of the microcirculation which are comparable to those achieved with intravital fluorescence videomicroscopy (IFM), but without the use of fluorescent dyes. The purpose of this study was to validate the Cytoscan Model E-II instrument against IFM. The experiments were carried out on striated muscle in the dorsal skinfold chamber of the awake Syrian hamster. The following parameters were measured in identical regions of interest in the same animal under baseline conditions and 0.5 and 2 h after a 4-hour period of pressure-induced ischemia: arteriolar diameter, venular diameter and venular red blood cell velocity. Bland-Altman plots showed good agreement between the two techniques for venular red blood cell velocity. As expected, arteriolar and venular diameters as measured by the Cytoscan were on average 5 microm smaller than the values from IFM, since the Cytoscan measures the red blood cell column width and IFM measures luminal diameter. Thus, OPS imaging can be used to make valid measurements of microvascular diameter and red blood cell velocity in tissues.

Animals↗
PubMedDate not supplied

Comparison of regional blood flow values measured by radioactive and fluorescent microspheres.

Fluorescent microspheres (FM) have become an attractive alternative to radioactive microspheres (RM) for the measurement of regional blood flow (RBF). The aim of the present study was to investigate the comparability of both methods by measuring RBF with FM and RM. Eight anaesthetised pigs received simultaneous, left atrial injections of FM and RM with a diameter of 15 microm at six different time points. Blood reference samples were collected from the descending aorta. RBF was determined in tissue samples of the myocardium, spleen and kidneys of all 8 animals. After radioactivity of the tissue samples was determined, the samples were processed automatically for measuring fluorescence using a recently developed filter device (SPU). RBF was calculated with both the isotope and spectrometric data of both methods for each sample resulting in a total of 10,512 blood flow values. The comparison of the RBF values yielded high linear correlation (mean r(2) = 0.95 +/- 0.03 to 0.97 +/- 0.02) and excellent agreement (bias 5.4-6.7%, precision 9.9- 16.5%) of both methods. Our results indicate the validity of MS and of the automated tissue processing technique by means of the SPU.

Animals↗
PubMedDate not supplied

Leukocyte-capillary plugging and network resistance are increased in skeletal muscle of rats with streptozotocin-induced hyperglycemia.

Although diabetic retinopathy is a leading cause of blindness, the mechanisms underlying the disorder remain unresolved. Recent studies have reported both an increase in viscosity and a decrease in filterability of blood in diabetes, as well as increased activation of monocytes and granulocytes. These rheological effects have been implicated in capillary closure which is an early pathological change in diabetic retinopathy. The objective of this study was to quantitatively measure in vivo for the first time the resistance increase in capillary networks due to leukocyte-capillary plugging during experimental diabetes. Intravital measurements of plugging durations and frequencies were made throughout capillary networks in the spinotrapezius muscle of anesthetized rats subject to streptozotocin (STZ) induced hyperglycemia. These data were used to estimate the increase in microvascular flow resistance due to leukocyte plugging. The increase averaged 13.0% which is significantly different (p < 0.05) from the 1.1% observed in previous experiments with normal rats. Although the total white cell count was normal, the diabetic animals exhibited a significantly increased percentage of monocytes. A small but significant decrease in capillary diameter in the diabetic animals was also observed. Thus, leukocytes have a significant impact on microvascular hemodynamics in diabetic animals, and leukocyte-capillary plugging may be an important mechanism of capillary closure and subsequent microvascular dysfunction in diabetic retinopathy.

Animals↗
PubMedDate not supplied

Kinetics of white blood cell staining by intravascular administration of rhodamine 6G.

Rhodamine 6G is a vital dye accumulating in the mitochondria of cells. It is used in intravital fluorescence microscopy for contrast enhancement of white blood cells (WBC), enabling visualization of WBC in the microvasculature even at high center flow velocity. The aim of this study was to examine the kinetics of WBC staining after intravascular administration of rhodamine 6G in Lewis rats, Syrian golden hamsters and BALB/c mice. For this purpose, WBC were isolated from whole blood and the percentage of cells stained positively as well as their fluorescence intensity were measured by flow cytometry 5, 15, 30 and 60 min after dye administration. Injection of 0.06-0.2 mg/kg body weight of rhodamine 6G resulted in staining practically all granulocytes and monocytes over the entire observation period of 60 min. Fluorescence intensity of WBC was adequate to be detected in an experimental setup for intravital fluorescence microscopy in the hamster dorsal skinfold chamber. The degree of WBC staining was different in the species studied, yielding a higher percentage of stained lymphocytes in rats than in mice and hamsters. Staining of lymphocytes declined within 60 min after rhodamine application, the loss of fluorescent label being most pronounced in hamster cells. After 15-30 min, relative fluorescence intensity of stained lymphocytes had decreased considerably, indicating the need for reinjection of the dye or limiting microscopic analysis to approximately 15 min after rhodamine 6G administration. While the intravascular injection of rhodamine 6G results in adequate staining of granulocytes and monocytes, only a fraction of lymphoid cells are stained.

Animals↗
PubMedDate not supplied

An improved intravital microscopy system.

The use of intravital microscopy as a tool for studying the microcirculation has increased greatly over the last several decades. Early microscopes provided the first pictures of the microcirculation, but were cumbersome to use and subjected the tissue to a high light intensity, a problem which has recently become the subject of much discussion. The goal of this project was therefore to build a more ergodynamic microscope which minimizes the light exposure to the tissue. The automation of the microscope controls provides a platform on which other options can be built into the microscope, such as an autofocus feature. Furthermore, the use of the Optimas software also opens the possibility for on-line data processing.

Arterioles↗
PubMedDate not supplied

Mometasone furoate nasal spray is rapidly effective in the treatment of seasonal allergic rhinitis in an outdoor (park), acute exposure setting.

The objective of this study was to determine the time to onset of symptom relief following a single dose of mometasone furoate nasal spray (MFNS) in symptomatic patients with seasonal allergic rhinitis (SAR). This was a single-center, placebo-controlled, double-blind, randomized, parallel-group study with a 7-day run-in period followed by a single-dose administration of medication or placebo in an outdoor park setting. The park site provided an acute exposure to seasonal (tree and grass) pollens. Patients remained in the park of approximately 12 hours after dosing, during which time hourly assessments of SAR symptoms were recorded on a diary card. Two hundred thirty-nine patients with symptoms of SAR entered the study. Patients receiving any concurrent medication for treatment of their symptoms were excluded. Patients were randomized in a 1:1 ratio to receive treatment with either a single dose of MFNS (200 micrograms/or matching placebo nasal spray. Outcome measures included an assessment of overall therapeutic response and change from baseline in total nasal plus non-nasal sign/symptom severity score, total nasal sign/symptom severity score, and total non-nasal sign/symptom severity score. Improvement in total nasal symptom scores, total non-nasal symptom scores, and total nasal plus non-nasal symptom scores were greater and more sustained in patients receiving MFNS than in patients receiving placebo. The mean decrease from baseline in total nasal plus non-nasal symptom scores was significantly greater in MFNS-dosed patients than in placebo-dosed patients at 5 hours after dosing (p < 0.01). The mean decrease from baseline in total nasal symptom scores was significantly greater in MFNS-dosed patients than in placebo-dosed patients at 7 hours after dosing (p < 0.01). The between-treatment differences in total nasal plus non-nasal symptom scores and total nasal symptom scores remained significant for all subsequent hourly assessments through 12 hours post-dose. Patient assessments of overall response to therapy at end point were significantly different between treatment groups (p < 0.01) with 60.5% of MFNS-treated patients reporting complete, marked, or moderate relief compared with 46.5% of placebo-treated patients. Mometasone furoate nasal spray produces a statistically significant improvement in nasal symptom scores in patients with SAR by 7 hours after administration of a single 200 micrograms dose (100 micrograms in each nostril).

Administration, Topical↗
PubMedDate not supplied

Effect of the long-acting somatostatin analogue SMS 201-995 (Sandostatin) in advanced breast cancer.

Sixteen post-menopausal patients with advanced breast cancer were treated with a long acting somatostatin analogue, SMS 201-995 (Sandostatin): 0.1 mg bid sub-cutaneously. The dose was chosen on the basis of efficiency in acromegaly treatment. SMS 201-995 activity was evaluated assaying Insulin Growth Factor 1 (IGF1) plasma concentration. A merely partial IGF1 decrease was noted. To be evaluable for response, patients had to be treated for at least 30 days. Among the 14 evaluable patients, we observed no response to SMS 201-995. However, we noted tumor stabilization in 3 patients after a 90 days treatment period. Side-effects were very mild. This first report on SMS 201-995 treatment of breast cancer suggests that further studies evaluating the effect of other modes of administration or drug association should be warranted.

Adult↗