Plasma exchange in acute renal transplant rejection.
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Acute Disease↗
Biomedical subjects
D Sutton
Publications and source records attributed to D Sutton.
Target antigens of anti-platelet antibodies in patients with acute, steroid-resistant ITP. The Canadian Apheresis Study Group.
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Acute Disease↗
A microcomputer system for the analysis of dental radiographs.
A system for the digital storage and computer analysis of dental radiographs is described. The system is based on popular microcomputer, of a type commonly used for other purposes in general dental practice. The analysis system includes methods to compensate for variations due to exposure and development in serial radiographs. Interactive software allows a detailed analysis of the radiograph, producing qualitative and quantitative data for diagnosis and monitoring. An example of its application is given.
Alveolar Process↗
Prodrugs of the selective antiherpesvirus agent 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (BRL 39123) with improved gastrointestinal absorption properties.
Potential oral prodrugs of the antiherpesvirus acyclonucleoside 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (1, BRL 39123) have been synthesized and evaluated for bioavailability of 1 in the blood of mice. Reduction of 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-amino-6-chloropurine (13) using ammonium formate and 10% palladium on carbon afforded the 2-aminopurine 14, which was hydrolyzed to the monoacetate 15 and to 2-amino-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purine (5). The 2-aminopurine 5 was subsequently converted to additional monoester (17, 21-23) and diester (16, 24) derivatives and to its di-O-isopropylidene derivative 18. Both 5 and its esters (14-17, 21, 22) and also 18 were well absorbed after oral administration and converted efficiently to 1, the diacetyl (14) and dipropionyl (16) esters providing concentrations of 1 in the blood that were more than 15-fold higher than those observed after dosing either 1 or its esters (25-27). Some 6-alkoxy-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines (8-10), the preparation of which has been reported previously, also showed improved absorption properties, but their conversion to 1 was less efficient than for the 2-aminopurine derivatives. On the basis of these results and subsequent experiments involving determinations of rates of conversion to 1 in the presence of rat and human tissue preparations, 9-[4-acetoxy-3-(acetoxymethyl)but-1-yl]-2-aminopurine (14, BRL 42810) was identified as the preferred prodrug of 1. Oral bioavailability studies in healthy human subjects confirmed 14 as an effective prodrug, and this compound is now being evaluated in clinical trials.
2-Aminopurine↗
Selection of an oral prodrug (BRL 42810; famciclovir) for the antiherpesvirus agent BRL 39123 [9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine; penciclovir].
The limited oral absorption in rodents of the antiherpesvirus agent 9-(4-hydroxy-3-hydroxymethylbut-l-yl)guanine (BRL 39123 [penciclovir; British approved name]) prompted a search for oral prodrugs. The 6-deoxy derivative of penciclovir (BRL 42359) and the corresponding diacetyl and dipropionyl 6-deoxy derivatives (BRL 42810 [famciclovir; British approved name] and BRL 43599) were tested as oral prodrugs. The in vivo absorption (dose, 0.2 mmol/kg) and the conversion to the active compound, penciclovir, were determined in rats. Compared with the sodium salt of penciclovir given intravenously, the bioavailabilities of penciclovir from orally administered penciclovir, BRL 42359, famciclovir, and BRL 43599 were 1.5, 9, 41, and 27%, respectively. These prodrugs and 6-deoxyacyclovir were tested for stability in rat duodenal contents and for metabolism in rat intestinal wall homogenate, liver homogenate, and blood and in the corresponding human fluids and tissues. Famciclovir was much more stable than BRL 43599 in human duodenal contents (half-lives, greater than 2 h and 7 min, respectively) yet was efficiently converted to penciclovir by the tissue homogenates. The major metabolic pathway was by deacetylation followed by oxidation at the 6 position. The rate of oxidation was comparable to that of 6-deoxyacyclovir, which is known to be converted efficiently to acyclovir in humans. Famciclovir was selected for further evaluation and progression to studies in humans. These subsequent studies confirmed that, after oral dosing with famciclovir, more than half the dose was absorbed and rapidly converted to penciclovir.
2-Aminopurine↗
Dynamic viscous flow in distensible vessels of skeletal muscle microcirculation: application to pressure and flow transients.
Blood flow in the microcirculation of the rat skeletal muscle during transient changes of arterial pressure is analyzed theoretically. Although flow in such small vessels is quasi-steady and has a very low Reynolds number, time-dependent nonuniform flows along the length of the blood vessels can be observed due to vessel distensibility. The governing equations for a single microvessel are derived using previously measured microvessel elasticity, and several solutions to different inflow and outflow pressures and flow conditions are investigated. The results indicate that when such distensible microvessels are subjected to a step increase of arterial pressure, the arterial flow shows a rapid overshoot followed by a progressive decay to steady-state. An arterial step flow induces a different response which takes the form of a monotonically increasing pressure. Pressure and flows are nonuniform along the vessel length during such transients. In-vitro whole organ pressure-flow data are presented in the dilated rat gracilis muscle which qualitatively agree with the theoretical predictions.
Animals↗
Hyperviscosity syndrome in a patient with acquired immunodeficiency syndrome.
The hyperviscosity syndrome is most commonly seen in association with monoclonal gammopathies and has only rarely been described in association with polyclonal hypergammaglobulinemia. We have recently seen a patient with known acquired immunodeficiency syndrome who presented with the hyperviscosity syndrome in the setting of polyclonal hypergammaglobulinemia. To our knowledge, this is the first reported case of a patient with the acquired immunodeficiency syndrome and the hyperviscosity syndrome. The case is presented and the pathogenesis and implications of this diagnosis are discussed.
Acquired Immunodeficiency Syndrome↗
Myofibroblasts in head and neck surgery. An experimental and clinical study.
Myofibroblasts in human granulation tissue have many of the structural and functional characteristics of smooth-muscle cells and appear to be responsible for wound contraction. They have also been identified in contracted scar tissue in nongranulation wounds. In this report, their role in head and neck wound healing will be explored utilizing transmission electron microscopy and immunoperoxidase techniques with antibodies to the intermediate filament vimentin and to muscle-restricted actins. In piglets, high-tension, low-tension, and granulating wounds were created and studied with serial biopsy specimens. Results showed few myofibroblasts in either the high- or low-tension wounds and multiple myofibroblasts in the granulating wounds. In the clinical studies, the immunoperoxidase technique with monoclonal antibody to muscle-specific actins proved most useful in identifying myofibroblasts. Myofibroblasts were present in granulating wounds and hypertrophic scars. They were not widely present in mature keloids.
Animals↗
Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl) guanine (BRL 39123) in animals.
The antiviral activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) was assessed in several animal models of herpes simplex virus (HSV) infection. BRL 39123 was as active as acyclovir (ACV) when applied topically to guinea pigs with a cutaneous HSV type 1 (HSV-1) infection and was also active topically in an HSV-2 genital infection. Before systemic administration to infected animals, BRL 39123 and ACV were administered orally and subcutaneously to mice, and the blood was assayed for each compound by high-pressure liquid chromatography. When given systemically to mice infected cutaneously with HSV-1, BRL 39123 was as active as ACV. In mice infected intranasally with HSV-1 or HSV-2, single daily subcutaneous doses of BRL 39123 were more effective than equivalent treatment with ACV, reflecting the more persistent activity seen in cell culture and a more stable triphosphate within the infected cell. When the compounds were supplied in drinking water for this infection, BRL 39123 and ACV had similar potencies against HSV-1, although ACV was more active against an HSV-2 infection than BRL 39123 was. In mice infected intraperitoneally with HSV-1, BRL 39123 was 10-fold more potent than ACV and a single dose of BRL 39123 reduced virus replication within the peritoneal cavity more effectively than 3 doses of ACV given 1, 5, and 20 h after infection. Although BRL 39123 failed to eradicate the virus from mice latently infected with HSV-1, treatment initiated 5 h after infection of the ear pinna reduced the numbers of mice that developed latent infections.
Acyclovir↗
Reflux oesophagitis and oesophageal transit: evidence for a primary oesophageal motor disorder.
Patients with reflux oesophagitis have a diminished capacity for distal oesophageal clearance. This is considered to be secondary to acid reflux damage to the oesophageal wall. We have postulated that the observed oesophageal dysmotility is a primary phenomenon. Using 24 hour oesophageal pH monitoring and the solid bolus oesophageal egg transit test, we evaluated the oesophageal transit of 55 patients, with symptomatic reflux oesophagitis, and 16 healthy volunteers. The transit for the entire oesophagus was significantly prolonged in the patient group. This delay was evident in all three segments of the oesophagus. Amongst the patients, there was significant correlation between the oesophageal transit time and the number of prolonged reflux events. No correlation was found, however, between symptom score or severity of endoscopic oesophagitis and transit time. These results would indicate that the oesophageal dysmotility is an integral part of gastrooesophageal reflux disease, and is more of a cause than an effect.
Adolescent↗
New physiological method of evaluating oesophageal transit.
A method of measurement of oesophageal transit time in the upright posture of a chewed solid bolus has been developed and assessed in normal volunteers (n = 16) and in 32 patients with oesophageal disease: organic stricture (n = 5), oesophageal motility disorders (n = 19) and reflux oesophagitis without stricture formation (n = 8). The test involves swallowing a 10 ml poached egg white bolus labelled with 99mTc sodium pertechnetate and external scanning by a gamma camera. An on-line computer program allows detailed analysis by the condensed image technique (which demonstrates the pattern of oesophageal transit) and activity-time curves for the whole, the upper, middle and lower thirds of the oesophagus. The reproducibility of the test is good (coefficient of variation of the total transit of 14 per cent). The results on the normal volunteers have shown that oesophageal transit slows in an aboral direction with transit being faster in the upper, when compared with the middle and lower thirds. The test clearly differentiates patients with oesophageal disease from the normal. The condensed image analysis appears to be useful in outlining the pattern of transit in patients with motility disorders. Patients with reflux oesophagitis have delayed oesophageal transit.
Adult↗
The solid bolus oesophageal egg transit test: its manometric interpretation and usefulness as a screening test.
The standardized 99mTc-labelled solid bolus oesophageal egg transit test (OET) was developed for assessing oesophageal motility. Its value in detecting oesophageal motility disorders was compared with oesophageal manometry in 102 symptomatic patients. Of 32 patients with normal OET, 22 (68.8 per cent) had normal manometry, whereas of 61 patients with abnormal manometry, 51 (84 per cent) had abnormal OET (chi 2 = 15.82, P less than 0.001). The computer-generated condensed image of the OET clearly defined five transit patterns: normal (n = 32); oscillatory (n = 21); non-clearance (n = 16); 'step' delay (n = 16) and non-specific delay (n = 17). The oscillatory pattern occurred in only one patient with normal manometry, but in all six with manometrically defined achalasia and two with diffuse oesophageal spasm. The predictive value of a positive (abnormal) OET test in detecting abnormal motility (both specific and non-specific disorders) was 73 per cent, and for specific motility disorders was 100 per cent. The predictive value of a negative (normal) test in excluding specific motor disorders was 94 per cent. Manometric tertiary contractions and low amplitude waves occurred in 6/32 and 1/32 patients with normal OET but in 31/70 and 21/70 with abnormal OET (chi 2 = 5.14, P less than 0.02; chi 2 = 7.85, P less than 0.001 respectively). Patients showing oscillation demonstrated significantly more tertiary contractions (17/21) and low amplitude waves (12/21) compared with 20/81 and 10/81 patients without oscillation (chi 2 = 20.47, P less than 0.001; chi 2 = 17.22, P less than 0.001 respectively). The solid bolus oesophageal transit test provides an objective screening test of specific oesophageal motility disorders and should be performed before oesophageal manometry.
Adult↗
Antiherpesvirus activity of 9-(4-hydroxy-3-hydroxy-methylbut-1-yl)guanine (BRL 39123) in cell culture.
The activity of 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (BRL 39123) against several herpesviruses was compared with that of acyclovir (ACV). In plaque reduction tests with clinical isolates of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), and varicella-zoster virus, mean 50% inhibitory concentrations (IC50S) (n = number tested) for BRL 39123 were 0.4 (n = 17), 1.5 (n = 13), and 3.1 (n = 5) micrograms/ml, respectively. Corresponding IC50S for ACV were 0.2, 0.6, and 3.8 micrograms/ml. Cytomegalovirus was relatively resistant to BRL 39123 (IC50, 51 micrograms/ml), but equid herpesvirus 1, bovid herpesvirus 2, and felid herpesvirus 1 were susceptible (IC50S, 1.6, 1.2, and 0.9 micrograms/ml, respectively). BRL 39123 was inactive against an HSV-1 strain which does not express thymidine kinase activity, but a DNA polymerase mutant selected for resistance to ACV was sensitive to BRL 39123 (IC50, 1.5 micrograms/ml). In contrast to the results from plaque reduction tests, BRL 39123 was more active than ACV against HSV-1 and of equal activity against HSV-2 in virus yield reduction assays in MRC-5 cells. After treatment of HSV-infected cultures for short periods, BRL 39123 was considerably more effective than ACV at reducing virus replication, and furthermore, after removal of extracellular BRL 39123, virus replication remained depressed for long periods, whereas such persistent activity was not observed with ACV. Neither compound significantly affected MRC-5 cell replication at 100 micrograms/ml, but at 300 micrograms/ml BRL 39123 was more inhibitory than ACV.
Acyclovir↗
Improvement of the bioavailability of the anti-herpes virus agent BVDU by use of 5'-O-alkoxycarbonyl derivatives with increased metabolic stability.
(E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was found by HPLC analysis to be rapidly metabolized in mice and in liver homogenates from mouse and man to the antivirally inactive (E)-5-(2-bromovinyl) uracil (BVU) but was comparatively stable in blood from both species. Of a series of 5'-O-alkoxycarbonyl derivatives of BVDU, the 5'-O-tert.-butoxycarbonyl derivative (BRL 37000) was the most stable in mouse and human blood and liver homogenates, neither its ester bond nor its N-glycosidic linkage being readily cleaved enzymically. Oral administration of BRL 37000 and the 5'-O-ethoxycarbonyl derivative (BRL 36101) to mice gave prolonged serum concentrations of BVDU and delayed the appearance of BVU compared with the BVDU control. BRL 36101 was more active than BVDU when administered orally to mice infected cutaneously with herpes simplex virus type 1.
Animals↗
Indium-111 leukocyte scanning for myocarditis.
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Humans↗
Vestibular effects of electrical stimulation of the cochlea. Monitored in the awake primate.
The effect of electrical stimulation of the cochlea on vestibular response was monitored in six rhesus monkeys. Eye movements and single-unit activity from the vestibular portion of the eighth nerve, vestibular nuclei, reticular formation, and abducens nucleus were observed while electrical stimulation was delivered through an implanted cochlear prosthesis. In one animal of this series, neural activity from the inferior colliculus and cochlear nuclear complex was also recorded. Electrical stimulation elicited eye-movement responses in only one animal. In the animals from which single-unit activity was recorded, no positive vestibular effects were noted. In one animal of this study, responses were elicited from auditory structures by relatively low intensities of electrical stimulation.
Acoustic Stimulation↗