Search PubMed⌕ Search

Biomedical subjects

R N Saunders

Publications and source records attributed to R N Saunders.

At least 19 recordsLinked to original sources
PubMed2003

The impact of cyclosporine dose reduction with or without the addition of rapamycin on functional, molecular, and histological markers of chronic allograft nephropathy.

BACKGROUND: Overexposure to cyclosporine is a risk factor for chronic allograft nephropathy (CAN) and dose reduction has been advocated. The purpose of this study was to determine the impact of adding the non-nephrotoxic immunosuppressant, rapamycin, after cyclosporine dose reduction in renal-allograft recipients with CAN. METHODS: Thirty-one patients with biopsy-confirmed CAN were prospectively randomized to receive a 40% cyclosporine dose reduction with (rapamycin, n=16) or without (control, n=15) the addition of rapamycin 2 mg/day. Renal function and side-effect parameters were assessed. Patients had renal allograft biopsies taken at recruitment and after 6 months. Glomeruli were isolated from these and underwent total mRNA extraction followed by RT-PCR-ELISA to assess transforming growth factor-beta1, collagen III, TIMP-1, TIMP-2, and matrix metalloproteinase-2 expression. Samples were also stained with Sirius red and the percentage interstitial volume fraction quantified by computerized histomorphometric analysis. Data are presented as mean (+/-SD). RESULTS: Patient characteristics and cyclosporine trough levels after dose reduction (rapamycin 68 [+/-21] vs. control 56 [+/-19] ng/mL, P=NS) were similar in both groups. Rapamycin patients had a significant fall in Cr-51 radioisotope glomerular filtration rate (31.6 [+/-8.9] to 27.3 [+/-8.6] mL/min, P<0.01) that was not significant in controls (29.5 [+/-10.4] to 27.0 [+/-8.0] mL/min, P=NS). Transforming growth factor-beta1 expression fell over time in control but remained constant in rapamycin patients. Conversely collagen III expression increased over the 6-month follow-up in rapamycin patients but not in controls. Both had comparable increases in TIMP-1 and matrix metalloproteinase-2 but only rapamycin patients developed a significant increase in TIMP-2. Sirius red-stained interstitial volume fraction fell over the study in controls (15.3-11.2%, P=0.06) but not in rapamycin patients (16.2-16.3%, P=NS). CONCLUSION: Rapamycin (2 mg/day) did not improve functional, molecular, or histological outcome in patients with CAN after cyclosporine dose reduction. Further studies involving larger numbers of patients are necessary to confirm these findings.

Adult↗
PubMed2001

A case-control comparison of the results of renal transplantation from heart-beating and non-heart-beating donors.

INTRODUCTION: The decline in heart-beating brainstem dead organ donors has necessitated the search for other organ sources. In the field of renal transplantation one alternative source currently available, but little used, is that of kidneys from non-heart-beating donors (NHBD). Reticence to use NHBD kidneys is in part due to concerns over the effect that warm ischemic may have subsequent graft function. Presented here are the results of the NHBD renal transplants at the Leicester transplant unit, and compared with matched heart-beating donor transplants as a case control analysis. METHODS: In order to analyze any differences in graft performance between the two organ sources, the confounding effect of other variables known to influence the outcome of renal transplantation was minimized by matching NHBD and HBD transplants for the following criteria: donor age and sex, first or re-transplant, anastomosis and cold times, tissue match and PRA sensitisation. Transplant performance was assessed primarily by graft survival, the statistical evaluation of which was by log rank analysis of Kaplan-Meier curves. RESULTS: 72 NHBD and 192 HBD transplants were performed over an eight year period. Of the 192 HBD transplants, 105 matched one or more of the NHBD by the criteria outlined above, and thus constituted the control group for comparison. There was no significant difference in overall graft survival between the two groups. The 5 year survival for the NHBD was 73% compared with 65% for HBD kidneys. When death with a functioning graft is treated as censored data, then these figures become 75% and 81% respectively, again without statistical significance. CONCLUSION: NHBD kidneys are a valuable additional source of organs for transplantation, with long-term survival, comparable to transplants from HBD.

Acute Disease↗
PubMed2001

Bilateral absence of the superior vena cava.

Congenital anomalies of the superior vena cava are rare and often coexist with other cardiac abnormalities. In this report, we present a case of absent bilateral superior vena cava with no associated cardiac anomaly. Blood from the arms, head, and upper torso returned to the right atrium through the azygos vein and the inferior vena cava, mimicking chronic superior vena cava obstruction.

Adult↗
PubMed2001

Rapamycin in transplantation: a review of the evidence.

Rapamycin in transplantation: A review of the evidence. The calcineurin inhibitors have been the mainstays of immunosuppression for solid organ transplantation over the last two decades, but nephrotoxicity limits their therapeutic benefit. Rapamycin is a new drug with both immunosuppressant and antiproliferative properties that has a unique mechanism of action distinct from that of the calcineurin inhibitors. It has a role as a maintenance immunosuppressant either alone or in combination with a calcineurin inhibitor and can also be used to treat refractory acute rejection. Theoretical evidence suggests that it may limit the development and progression of chronic rejection in transplant recipients, but this has yet to be confirmed. This review examines the current in vitro animal and human work underlying the use of rapamycin and, in addition, comments on the pharmacokinetics and side-effect profile of this promising new agent.

Animals↗
PubMed2000

Workload generated by a living donor programme for renal transplantation.

BACKGROUND: The ethical and medical implications of live kidney donation result in a comprehensive work-up process. The aim of this study was to determine the magnitude of the workload and the yield of renal transplants generated by a live donor programme. METHODS: Referrals to the Leicester live donor programme over the five-year period 1994-1998 were retrospectively assessed. These were initiated by nephrology referral and subsequently investigated in a stepwise manner. Patients were counselled and baseline tests performed prior to consultant surgeon review and assessment of donor renal function/anatomy. RESULTS: One hundred and fifty referrals consisting of 150 recipients with 269 potential donors were originally made. This resulted in 32/120 (27%) related and 3/30 (10%) unrelated recipients (P=0.06) and 32/220 (15%) related and 3/49 (6%) unrelated donors proceeding to live donor transplantation, with a mean work-up time (+/-SD) of 9 (+/-7) months. One hundred and fifteen recipients (77%) and 234 (87%) donors failed to proceed at various stages of assessment, for a variety of immunological, medical and social reasons. A large number of expensive immunological investigations were required for potential donors, the majority of which did not proceed to transplantation. However as a result of performing these in the early stages of assessment the number of more invasive tests is kept to a minimum. CONCLUSIONS: There is a relatively low yield of transplants from live donor referrals, particularly those between unrelated individuals. The vast majority of referrals fail to proceed for legitimate reasons, but as a result, create a significant workload with notable staffing and financial implications.

Health Care Costs↗
PubMed1989

Release of platelet-activating factor from ischemic-reperfused rabbit heart.

This study shows that platelet-activating factor (PAF) is released in significant amounts (10.9 +/- 12.8 ng/min) during the initial reperfusion of the ischemic-isolated rabbit heart. When reperfusion was performed in the presence of autologous rabbit platelets, the electrical and mechanical alterations characteristic of this phase were significantly worsened. These alterations were antagonized by pretreatment of rabbit platelets with a PAF receptor antagonist (SDZ 63-675), suggesting a contribution of PAF released during reperfusion in the cardiac dysfunction. To discriminate whether the effect of PAF was platelet dependent, infusion of PAF (10-40 ng) was performed in nonischemic rabbit hearts perfused with or without autologous platelets. Although the effect of PAF per se was minimal, in the presence of platelets PAF induced a biphasic effect characterized by a transient positive inotropism followed by a dose-dependent decrease in coronary flow, negative inotropism, reduction of action potential duration, and conduction arrhythmias. These effects were abolished by pretreatment of platelets with SDZ 63-675, suggesting a PAF receptor-mediated platelet activation. In addition, a relative contribution of histamine, thromboxanes, and leukotrienes released from activated platelets was inferred by experiments performed with pyrilamine and cimetidine, imidazole, and FPL 55712, respectively.

Animals↗
PubMed1989

Effects of combined receptor antagonists of leukotriene D4 (LTD4) and platelet-activating factor (PAF) on rhesus airway responses to LTD4, PAF and antigen.

Rhesus monkeys with IgE-mediated asthmatic-type responses to Ascaris suum antigen were pretreated with a combination of 2 receptor antagonists to leukotriene D4 (LTD4) and platelet-activating factor (PAF). This combination of anti-LTD4 and anti-PAF was shown to inhibit airway responses to either LTD4 or PAF in separate experiments in these Ascaris airway-reactive animals. When the same combination of LTD4 and PAF receptor antagonists was used to pretreat the same animal prior to aerosol challenge with Ascaris antigen we could not demonstrate inhibition of the antigen-induced airway response. Thus, combined receptor blockade for LTD4 and PAF did not alter IgE-mediated acute airway responses to antigen in this species. We review the current status of rhesus asthma and LTD4 and PAF receptor antagonist activity in this model.

Animals↗
PubMed1988

Biological effects of the orally active platelet activating factor receptor antagonist SDZ 64-412.

SDZ 64-412 is a trimethoxyphenylethylphenyl imidazo[2,1-a] isoquinoline molecule that displays marked in vitro inhibition of platelet activating factor (PAF)-induced human platelet aggregation (IC50 = 60 nM) but is without inhibition (at 100 microM) of epinephrine-, ADP- or collagen-induced aggregation. SDZ 64-412 antagonized receptor binding of radiolabeled PAF to human platelet membranes with an IC50 = 60 nM. In the rat, SDZ 64-412 inhibited 100 ng kg-1 PAF-induced hypotension when given i.v. (ED50 = 0.23 mg kg-1) or p.o. (ED50 = 13 mg kg-1). In the guinea pig, SDZ 64-412 inhibited 50 ng kg-1 PAF-induced bronchoconstriction (ED50 = 4.2 mg kg-1 p.o.) and hemoconcentration (ED50 = 5.0 mg kg-1 p.o.). SDZ 64-412 exhibited oral activity in the dog against 1.5 micrograms kg-1 PAF-induced hypotension (ED50 = 5.1 mg kg-1 p.o.) and hemoconcentration (ED50 = 4.9 mg kg-1) and 3.5 micrograms kg-1 PAF-induced hemoconcentration in the cebus primate (ED50 = 12.8 mg kg-1 p.o.). SDZ 64-412 protected in a dose-dependent manner against PAF-induced lethality (LD75 = 75 micrograms kg-1 i.v.) in mice, where 20 mg kg-1 p.o. improved survival from 25 +/- 4% to 77 +/- 8%. SDZ 64-412 afforded complete protection against endotoxin-induced lethality (LD90 = 7.5 mg kg-1 endotoxin i.v.) where the ED50 was 45 mg kg-1 twice predose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1987

Inhibition by SRI 63-072 and SRI 63-119 of PAF-acether and immune complex effects in the guinea pig.

We have examined two PAF-acether receptor antagonists, SRI 63-072 and SRI 63-119, for their ability to inhibit PAF-acether and immune complex effects in the guinea pig. Both compounds exhibited dose-dependent inhibition of bronchoconstriction and hemoconcentration induced by 0.1 micrograms kg-1 PAF-acether, where the ED50 values of SRI 63-072 were 0.3/0.4 mg kg-1 i.a. and 0.14/0.17 mg kg-1 i.a. for SRI 63-119 for each response, respectively. The d and 1 chiral forms of both antagonists were equipotent towards inhibition of hemoconcentration and bronchoconstriction, suggesting a lack of enantiomeric selectively. SRI 63-072 was further evaluated for its ability to inhibit dermal extravasation in the reverse passive Arthus reaction. Guinea pigs given 125I-BSA i.v as antigen and anti-BSA antibodies by intradermal injection exhibited plasma leakage that was dose- and time-dependent relative to the antibody amount. SRI 63-072 exhibited 46% maximal inhibition of dermal plasma leakage when injected in the skin (100 micrograms site-1 i.d.) with the antibody but less than 10% inhibition when administered intra-arterially (3.0 mg kg-1 i.a.) with the antigen. Therefore, these antagonists effectively inhibit systemic effects of PAF-acether and are partially effective towards inhibition of the dermal extravasation induced by immune complexes. Furthermore, unlike the enantiomeric differences between R and S PAF-acether, the chiral molecules of 63-119 and 63-072 effectively antagonized hemoconcentration and bronchoconstriction induced by PAF-acether.

Administration, Oral↗
PubMed1987

In vitro and in vivo pharmacological profiles of the PAF receptor antagonist SRI 63-675.

We have examined a recently developed PAF antagonist SRI 63-675 (dimethyl-tetrahydrofuran-methoxyphosphinyloxy-ethylquinolinium ) for its ability to inhibit several major PAF-induced physiological responses. The compound was a potent inhibitor of PAF-induced platelet aggregation in platelet rich plasma obtained from humans, guinea pigs, and rabbits, with IC50 values of 3.43, 0.25, and 0.97 microM, respectively. SRI 63-675 did not inhibit ADP, collagen nor epinephrine-induced human platelet aggregation. The IC50 for inhibition of PAF receptor binding to human platelets was 0.37 microM. In the rat SRI 63-675 inhibited 0.1 microgram kg-1 i.v. PAF-induced hypotension, with an ED50 of 32 micrograms kg-1 i.v. Using the same PAF challenge in the guinea pig, SRI 63-675 inhibited the hemoconcentration (ED50 = 17 micrograms kg-1 i.v.) and bronchoconstriction (ED50 = 24 micrograms kg-1 i.v.) responses. In the primate, the ED50 was 28 micrograms kg-1 i.v. against 3.5 micrograms kg-1 PAF-induced hemoconcentration. The ratio (1:6) in the primate of PAF used (6.3 nmol kg-1) to antagonist at the ED50 (40.7 nmol kg-1) indicates exceptional potency of SRI 63-675 in this species. The inhibition by SRI 63-675 of the major PAF-induced effects in the rat, guinea pig and primate suggests a common receptor may be involved in the expression of these PAF responses.

Animals↗
PubMed1987

Biological properties of the antagonist SRI 63-441 in the PAF and endotoxin models of hypotension in the rat and dog.

Intravenous administration of platelet-activating factor (PAF) produces dose-dependent hypotension in several species. We have evaluated a recently developed PAF antagonist, SRI 63-441, for its ability to inhibit the hypotensive effect of PAF in the rat and dog. In the rat, 100 ng/kg PAF produced a 38.6 +/- 5.1% decrease in carotid mean arterial pressure (MAP), followed by a 3.2 +/- 0.7 min recovery period for MAP to return to baseline values. SRI 63-441 reduced the hypotension response in the rat, where the ED50 values for inhibition of MAP were 0.16 mg/kg i.v. and 0.19 mg/kg i.v. for the recovery period. Dogs challenged with 1.5 micrograms/kg PAF i.v. demonstrated a 52 +/- 8% decrease in MAP that persisted for at least 15 min. The ED50 for inhibition of MAP by SRI 63-441 was 0.20 mg/kg i.v. Following injection of tritium-labeled SRI 63-441, 56.8 +/- 2.4% of the dose was recovered in the urine and 43.2 +/- 8.9% in the feces in the rats while in dogs 38.7 +/- 5.6% and 60.9 +/- 23.5% of the dose was excreted in the urine and feces, respectively. In the rat model of endotoxin-induced hypotension, SRI 63-441 given 1 min after a 5 mg/kg endotoxin challenge (which produced a 52 +/- 7% decrease in MAP), reversed the systemic effects, with an ED50 of 0.18 mg/kg i.v. The ED50 for reversal 6 min after endotoxin injection was 0.01 mg/kg. These results of inhibition and reversal by SRI 63-441 strongly implicate PAF as a pivotal mediator of hypotension and shock.

Animals↗
PubMed1987

Release of platelet-activating factor from rabbit heart perfused in vitro by sera with transplantation alloantibodies.

During "hyperacute rejection" of rabbit heart perfused with transplantation alloantibodies, platelet activating factor (PAF) was released into the coronary effluent, which appeared to have physicochemical and functional properties similar to the 1-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (synthetic PAF) and to PAF obtained from IgE-sensitized rabbit basophils. The release of PAF was associated with an early tachycardia, followed by increasing bradycardia and conduction arrhythmias, as well as decrease of coronary flow and of amplitude of electrogram. The heart stopped beating within 30 min. The release of PAF as well as the "rejection" required the presence of fresh rabbit serum as a source of complement. The PAF receptor antagonist SRI 63-072 in a dose of 0.6 mg, reversed by 70% the reduction of coronary flow within 2-4 min after its addition to the perfusate; ED50 was 0.4 mg. Bradycardia and arrhythmia were reduced; however, the normal electrical activity was only occasionally restored. The cessation of heart action was delayed up to 50 min after the beginning of perfusion with transplantation alloantibodies and complement, but it was not prevented. These results suggest that PAF is released during "rejection" of the heart perfused in vitro with serum containing transplantation alloantibodies in the absence of inflammatory cells and that this mediator is at least in part responsible for the deterioration of cardiac function.

Animals↗
PubMed1987

Platelet-activating factor antagonists.

Over the past decade platelet-activating factor has achieved the status of an important inflammatory mediator. The scientific enthusiasm and number of research investigators, publications, and meetings recently devoted to PAF suggest that this mediator will be the subject of continued study in the foreseeable future. The potential for the presence and involvement of PAF in human disease is easily concluded from the reports described in this review. Both the need for low concentrations for cellular response and the rapid biological clearance mechanisms have made the proof of the involvement of PAF in human disease difficult. The discovery of PAF receptor antagonists and structure-activity relationships of such antagonists (159) will make this determination possible in the near future. The current PAF antagonists may be considered as first generation agents, since the most potent antagonist is still less than 1/100th as potent as PAF is as an agonist. The wide diversity of clinical applications from asthma to septic shock may also require antagonists with selective attributes such as delivery route (oral vs intravenous vs topical) or biological half-life (prolonged vs short). PAF may prove to be the key mediator of several poorly understood disease syndromes such as hyperacute organ transplant rejection, ischemic bowel necrosis (160), and adult respiratory distress syndrome. We must wait for clinical results to draw further conclusions.

Animals↗
PubMed1987

Evaluation of the effect of a platelet activating factor antagonist on platelet activating factor and Ascaris antigen-induced airway responses in rhesus monkeys.

An acute airway response to aerosolized platelet activating factor (PAF) can be induced in certain rhesus monkeys. This PAF airway response is completely inhibited by the PAF antagonist, SRI 63-441, in normal monkeys. After the completion of these studies showing inhibition of the PAF airway response, we evaluated whether the PAF antagonist could inhibit three types of acute IgE-mediated airway responses to Ascaris suum (A) in rhesus monkeys. The A aerosol test protocols used the following: a single A aerosol challenge system; a threshold dose of A challenge system, which consists of increasing A aerosol exposure until an airway response occurs; and two sequential A challenges in which the response to the second A challenge always occurs if there is a response to the first A challenge. When SRI 63-441 was tested as a potential antagonist of the A airway response in any of these three systems, no inhibition was shown.

Aerosols↗
PubMed1986

Inhibition of PAF-induced systemic responses in the rat, guinea pig, dog and primate by the receptor antagonist SRI 63-441.

Systemic administration of synthetic PAF produces a number of dose-dependent circulatory effects in a variety of species. We have evaluated a novel PAF antagonist, SRI 63-441, for its ability to inhibit PAF-induced effects in the rat, guinea pig, dog and primate. In the rat, a 100 ng kg-1 i.v. PAF challenge produced a (mean +/- 1 S.D.) 39 +/- 5% decrease in carotid blood pressure. Prior injection of SRI 63-441 inhibited this hypotensive response in a dose-dependent manner, with an ED50 of 0.15 mg kg-1 i.v. In the guinea pig, PAF at 100 ng kg-1 elicited a 50 +/- 8% increase in hematocrit and a 50 +/- 11% elevation in bronchial resistance. The ED50 values for inhibition by SRI 63-441 of these two physiological parameters were 0.012 mg kg-1 and 0.035 mg kg-1 i.a., respectively. Dogs challenged with 1.5 micrograms kg-1 PAF i.v. exhibited 28.7 +/- 6.5% increase in hematocrit 10 min after injection. The ED50 value for SRI 63-441 inhibition of hemoconcentration in the dog was 0.18 mg kg-1 i.v. In the primate model of PAF-induced hemoconcentration, controls responded to 3.5 micrograms kg-1 i.v. PAF with a 30 +/- 6% increase in hematocrit. Using the primates in a cross-over design, the ED50 of SRI 63-441 was 0.11 mg kg-1 i.v. At this ED50 value, the ratio of nmol kg-1 PAF used versus nmol kg-1 antagonist is approximately 1:25. The effectiveness of SRI 63-441 in these models suggest potential clinical applications in disease states involving hyperpermeability and pulmonary dysfunction.

Animals↗
PubMed1986

Vascular responses of platelet-activating factor in the Cebus apella primate and inhibitory profiles of antagonists SRI 63-072 and SRI 63-119.

We have evaluated several effects of intravenous administration of synthetic platelet-activating factor (PAF) in the non-human primate Cebus apella. Parameters measured were hemoconcentration (monitored by changes in hematocrit), thrombocytopenia (platelet counts), leukopenia (loss of buffy coat), bronchoconstriction (increased airway resistance to fixed airway ventilation), thromboxane A2 production (radioimmunoassay to thromboxane B2) and in vitro aggregation responses of platelets in platelet-rich plasma. Cebus platelets were refractory to PAF-induced aggregation (up to 50 microM) and there was no evidence of thrombocytopenia, elevated thromboxane B2 levels, loss of buffy coat or bronchoconstriction following systemic PAF injection. Animals exhibited reproducible but varying sensitivities to PAF-induced hemoconcentration, where 3.5-30 micrograms/kg PAF (6.6-57 nmol/kg) was required to produce 28-32% increased hematocrit range for the colony. Hemoconcentration induced by PAF in baboons and rhesus occurred at similar doses, suggesting comparable sensitivity. Prior administration of PAF receptor antagonists SRI 63-072 or SRI 63-119 at 3 mg/kg inhibited cebus hemoconcentration responses to 3.5 micrograms/kg PAF by 96% and 100%, respectively. The ED50 values were 0.95 and 0.60 mg/kg, respectively. These results suggest that the cebus exhibits a reproducible hemoconcentration effect to PAF and that these vascular responses can be inhibited by a PAF receptor antagonist.

Animals↗