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Biomedical subjects

R L Webb

Publications and source records attributed to R L Webb.

At least 19 recordsLinked to original sources
PubMed2006

Transplant center quality assessment using a continuously updatable, risk-adjusted technique (CUSUM).

Access to timely, risk-adjusted measures of transplant center outcomes is crucial for program quality improvement. The cumulative summation technique (CUSUM) has been proposed as a sensitive tool to detect persistent, clinically relevant changes in transplant center performance over time. Scientific Registry of Transplant Recipients data for adult kidney and liver transplants (1/97 to 12/01) were examined using logistic regression models to predict risk of graft failure (kidney) and death (liver) at 1 year. Risk-adjusted CUSUM charts were constructed for each center and compared with results from the semi-annual method of the Organ Procurement and Transplantation Network (OPTN). Transplant centers (N = 258) performed 59 650 kidney transplants, with a 9.2% 1-year graft failure rate. The CUSUM method identified centers with a period of significantly improving (N = 92) or declining (N = 52) performance. Transplant centers (N = 114) performed 18 277 liver transplants, with a 13.9% 1-year mortality rate. The CUSUM method demonstrated improving performance at 48 centers and declining performance at 24 centers. The CUSUM technique also identified the majority of centers flagged by the current OPTN method (20/22 kidney and 8/11 liver). CUSUM monitoring may be a useful technique for quality improvement, allowing center directors to identify clinically important, risk-adjusted changes in transplant center outcome.

Adolescent↗
PubMed2006

SRTR center-specific reporting tools: Posttransplant outcomes.

Measuring and monitoring performance--be it waiting list and posttransplant outcomes by a transplant center, or organ donation success by an organ procurement organization and its partnering hospitals--is an important component of ensuring good care for people with end-stage organ failure. Many parties have an interest in examining these outcomes, from patients and their families to payers such as insurance companies or the Centers for Medicare and Medicaid Services; from primary caregivers providing patient counseling to government agencies charged with protecting patients. The Scientific Registry of Transplant Recipients produces regular, public reports on the performance of transplant centers and organ procurement organizations. This article explains the statistical tools used to prepare these reports, with a focus on graft survival and patient survival rates of transplant centers--especially the methods used to fairly and usefully compare outcomes of centers that serve different populations. The article concludes with a practical application of these statistics--their use in screening transplant center performance to identify centers that may need remedial action by the OPTN/UNOS Membership and Professional Standards Committee.

Adolescent↗
PubMed2001

Angiotensin receptor blockers and the kidney: possible advantages over ACE inhibition?

This review deals with similarities and differences between the effects of ACE inhibitors and AT1-receptor blockers in the kidney. Specific receptor blockade has demonstrated that the beneficial effects of AT1 blockers arise from two mechanisms: the reduction of the AT1 receptor mediated response and the increase in plasma levels of Ang II through the AT1-receptor blockade, which leads to increased stimulation of the AT2 receptor (the so-called yin-yang effect). Both ACE inhibition and AT1-receptor blockade provide significant renal protection in the majority of experimental animal models of kidney diseases. AT1 receptor blockade may offer additional clinical benefits over ACE inhibitor treatment, particularly in the kidney, where AT1-receptor blockade does not cause the fall in glomerular filtration rate seen with ACE inhibitor treatment. A number of long-term clinical studies currently running should show the real value of this new class of compounds in the management of hypertension and associated cardiorenal diseases.

Angiotensin II↗
PubMed1998

Identification of a novel stress activated kinase in kidney and heart.

We have previously described the patterns of stress kinase activation in rat kidney and heart in response to ischemia/reperfusion (Yin et al., 1997, J. Biol. Chem. 272, 19943-19950). During the course of these studies, we observed the activation of a novel kinase capable of phosphorylating c-Jun on serines 63 and 73. The molecular weight of this kinase is approximately 37 kD, significantly below the molecular weight of all previously identified Jun N-terminal kinase (JNK) isoforms. The pattern of activation of this 37 kD kinase in response to ischemia/reperfusion in both kidney and heart is distinct from that of known JNK isoforms. Western analysis of human renal proximal tubular epithelial (RPTE) cells, using a non-isoform specific phospho-JNK antibody, revealed the phosphorylation (activation) of a 37 kD protein in response to hypoxia. The 37 kD protein in RPTE cells is phosphorylated by other stress stimuli capable of activating JNK. Western analysis of tissues, using a non-isoform specific JNK antibody, identifies a cross-reactive 37 kD protein expressed in the liver, thymus and lymph node which is likely to correspond to the 37 kDa stress-activated kinase. The results of this study have led to the identification of a potentially novel kinase closely related to JNK but showing a distinct pattern of activation.

Animals↗
PubMed1998

Effects of valsartan and hydrochlorothiazide alone and in combination on blood pressure and heart rate in conscious-telemetered spontaneously hypertensive rats (SHR).

The purpose of this study was to examine the effectiveness of combined administration of the angiotensin AT1 receptor antagonist valsartan, with the diuretic hydrochlorothiazide (HCTZ), on blood pressure in conscious spontaneously hypertensive rats (SHR). Both drugs were administered continuously via subcutaneously implanted osmotic minipumps alone or in combination for a period of 2 weeks. Mean arterial pressure and heart rate were monitored throughout the infusion interval by means of chronically-implanted radiotransmitters. Coadministration of a diuretic with valsartan potentiated the blood pressure lowering effect in conscious SHR. Responses varied in magnitude from additive (valsartan at 1 mg/kg/day + hydrochlorothiazide at 3 and 10 mg/kg/day) to synergistic (valsartan at 3 mg/kg/day + hydrochlorothiazide at 10 mg/kg/day). The greater blood pressure lowering seen in SHR receiving combination therapy was associated with only a transient increase in heart rate. A similar potentiation of the antihypertensive effect was seen during coadministration of hydrochlorothiazide (HCTZ) with the angiotensin converting enzyme inhibitor benazeprilat. Additivity was noted with benazeprilat at 1 mg/kg/day + hydrochlorothiazide at 3 mg/kg/day, whereas a higher dose of HCTZ resulted in a synergistic response. These findings suggest that the similar results obtained with angiotensin converting enzyme inhibitors and AT1 receptor antagonists are due to the capacity to which diuretic-induced activation of the renin angiotensin system occurs.

Animals↗
PubMed1998

Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats.

OBJECTIVE: To investigate the chronic effects of combined administration of an angiotensin II receptor antagonist (valsartan) and an angiotensin converting enzyme inhibitor (benazeprilat) on blood pressure and heart rate in conscious telemetered spontaneously hypertensive rats. METHODS: Blood pressure and heart rate were monitored (by radiotelemetry) during 2-week infusions of 0.5-10 mg/kg valsartan per day and 0.5-10 mg/kg benazeprilat per day, alone or in combination, into conscious spontaneously hypertensive rats. Also, responses of blood pressure in conscious spontaneously hypertensive rats to exogenous angiotensin I and II were determined. RESULTS: Synergistic antihypertensive effects were observed when valsartan and benazeprilat were coadministered at submaximal monotherapy doses in the range 0.5-1.5 mg/kg per day. For all combination groups, the area over the curve (mmHg x days) for lowering of blood pressure was significantly greater (synergy) than that predicted from the sum of the monotherapy responses. Combination therapy abrogated pressor responses to angiotensin I more effectively than did comparable doses of the monotherapies. CONCLUSIONS: These results demonstrate that combination therapy aimed at interrupting operation of the renin-angiotensin system simultaneously at multiple sites can prevent the partial escape which occurs during chronic angiotensin converting enzyme inhibitor monotherapy. Furthermore, multiple-site intervention results in a more efficacious antihypertensive response than that achieved with high doses of the individual monotherapies.

Angiotensin Receptor Antagonists↗
PubMed1998

Protective effects of valsartan and benazeprilat in salt-loaded stroke-prone spontaneously hypertensive rats.

These experiments examined the effectiveness of chronic blockade of the renin angiotensin system with either valsartan or benazeprilat on survival, blood pressure and end-organ damage in salt-loaded stroke-prone SHR. Valsartan or benazeprilat given continuously by subcutaneous osmotic minipump beginning at 10.5 weeks of age lowered blood pressure, as determined by radiotelemetry, prevented proteinuria, prolonged survival and decreased the severity of histopathological changes in the heart and kidney. These results indicate that angiotensin receptor blockade affords a similar degree of protection as inhibition of angiotensin converting enzyme in salt-loaded stroke-prone SHR. Furthermore, our results are consistent with a primary contribution of angiotensin II to the maintenance of blood pressure and support a principal role for angiotensin II-dependent mechanisms in the development of end-organ damage in the salt-loaded stroke-prone SHR.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney.

In this report we investigate the molecular mechanisms that contribute to tissue damage following ischemia and ischemia coupled with reperfusion (ischemia/reperfusion) in the rat heart and kidney. We observe the activation of three stress-inducible mitogen-activated protein (MAP) kinases in these tissues: p38 MAP kinase and the 46- and 55-kDa isoforms of Jun N-terminal kinase (JNK46 and JNK55). The heart and kidney show distinct time courses in the activation of p38 MAP kinase during ischemia but no activation of either JNK46 or JNK55. These two tissues also respond differently to ischemia/reperfusion. In the heart we observe activation of JNK55 and p38 MAP kinase, whereas in the kidney all three kinases are active. We also examined the expression pattern of two stress-responsive genes, c-Jun and ATF3. Our results indicate that in the heart both genes are induced by ischemia and ischemia/reperfusion. However, in the kidney c-Jun and ATF3 expression is induced only by ischemia/reperfusion. To correlate these molecular events with tissue damage we examined DNA laddering, a common marker of apoptosis. A significant increase in DNA laddering was evident in both heart and kidney following ischemia/reperfusion and correlated with the pattern of kinase activation, supporting a link between stress kinase activation and apoptotic cell death in these tissues.

Activating Transcription Factor 2↗
PubMed1997

Catastrophic antiphospholipid syndrome: response to repeated plasmapheresis over three years.

The catastrophic antiphospholipid syndrome (CAPS) is rare and usually fatal. In this report, we describe an unusual patient who, 31 years after experiencing an atypical preeclampsia-eclampsia presentation known today as the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), developed CAPS, which seemed to complicate a diagnosis of primary antiphospholipid syndrome. She responded to repeated plasmapheresis over 3 years. Anticoagulants, corticosteroids, intravenous gamma globulin, and intravenous cyclophosphamide had all failed to halt the progression of CAPS, but repeated plasmapheresis not only halted the condition, but it led to the reversal of a leukoencephalopathy. The relationship between HELLP syndrome and CAPS is discussed, and possible pathogenetic mechanisms that explain the efficacy of repeated plasmapheresis in this setting are suggested. It is postulated that perhaps plasmapheresis, through removal of cytokines or other mediators, disrupts the interaction between phospholipid-protein complexes and endothelial cells. Repeated plasmapheresis should be considered in the most refractory cases of CAPS when more conventional treatment regimens have failed.

Aged↗
PubMed1997

Effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme, CGS 30440, on blood pressure and cardiac hypertrophy in spontaneously hypertensive rats.

This study examined the long-term effects of CGS 30440 on blood pressure, heart rate, cardiac hypertrophy, and urinary parameters in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. Initial studies with CGS 30440 produced dose-related reductions in mean arterial pressure, with a dose of 30 mg/kg/day of CGS 30440 producing a maximal sustained response of 40 mm Hg. CGS 30440 significantly inhibited plasma angiotensin-converting enzyme (ACE) activity by 82% in WKY rats. In SHRs, lung ACE and renal neutral endopeptidase (NEP) were inhibited by >60 and >90%, respectively. Urinary cyclic guanosine monophosphate (cGMP) excretion was significantly increased by CGS 30440 in SHRs but was unaltered in WKY rats. One hour after the final dose of an 8-week regimen, blood pressure was 122 +/- 4 and 189 +/- 5 mm Hg in CGS 30440-treated (30 mg/kg/day) and vehicle-treated SHRs, respectively. Heart-rate responses were not different between treatment groups. Left ventricular hypertrophy (LV weight/body weight ratio) was reduced significantly in SHRs to 2.45 +/- 0.08 mg/g at 10 mg/kg/day and 2.26 +/- 0.07 mg/g at 30 mg/kg/day versus 2.91 +/- 0.09 mg/g in rats receiving only vehicle. These results demonstrate that CGS 30440 is a potent, orally active antihypertensive agent with a long duration of action. The cardiac hypertrophy of established hypertension in the SHRs was attenuated by CGS 30440. Thus CGS 30440, an orally active prodrug, has been shown to be a novel antihypertensive agent with dual ACE/NEP inhibitory activity in SHRs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

In vitro and in vivo evaluation of an endothelin inhibitor reveals novel K+ channel opening activity.

A low molecular weight endothelin (ET-1) inhibitor (Ex. 127, European Patent Application 404 525 A2, Takeda Chemical Ind., 1991), CGS 26061, was synthesized and evaluated to determine its mechanism of action. CGS 26061 (10 microM) failed to inhibit binding of [125I]ET-1 in porcine thoracic aorta and was without effect on ET-1-induced [3H]inositol phosphate accumulation in A7r5 cells. However, CGS 26061 relaxed porcine coronary arterial rings precontracted with ET-1. In addition, contractions to PGF2 alpha and low K+ (20 mM) but not high K+ were attenuated, suggesting that CGS 26061 (1, 10 microM) is a potassium channel opener. Patch-clamp experiments confirmed the K+ channel activity (0.1-10 microM). The originally re ported inhibition of ET-1-induced pressor responses by Ex. 127 (CGS 26061) was not replicated in the anesthetized dog or conscious rat nor was it shown to be antihypertensive in SHR. These data have identified CGS 26061 as a novel K+ channel opener with a unique cardiovascular profile.

Animals↗
PubMed1995

Effects of the ETB-selective antagonist IRL 2500 in conscious spontaneously hypertensive and Wistar-Kyoto rats.

The pharmacologic profile of a novel and selective ETB antagonist, IRL 2500 (N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alany l-L-tryptophan) was examined in conscious spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats. The initial vasodepressor response to endothelin-1 (ET-1) and IRL 1620 (0.5 nmol/kg, i.v.) was significantly reduced in conscious WKY rats pretreated with IRL 2500 (10 mg/kg, i.v.). The secondary and sustained pressor response to these agonists, however, was not altered by IRL 2500. The linear peptide antagonist BQ 788, although also inhibiting the initial depressor responses, attenuated the secondary pressor response to IRL 1620 and potentiated the pressor response to ET-1. IRL 2500, administered alone to naive conscious SHRs produced a -37 +/- 8 mm Hg reduction in blood pressure, followed by a secondary pressor response (+38 +/- 7 mm Hg) with a duration exceeding 90 min. Pretreatment with either the ETA-selective antagonist BQ 123 or with the nonselective ETA/ETB antagonist SB 209670 resulted in marked potentiation of the depressor response and significant attenuation of the secondary rise in pressure. These results indicate that in the conscious rat, IRL 2500 acts as an ETB1-selective antagonist. In addition, ETA receptor activation contributes to the sustained pressore response to IRL 2500 in the conscious SHR. Furthermore, IRL 2500 may also exert a non-ET receptor-mediated vasodilation in the SHR.

Animals↗
PubMed1994

Pharmacological profile of a non-peptidic dual inhibitor of neutral endopeptidase 24.11 and endothelin-converting enzyme.

CGS 26303 is a potent and structurally unique non-peptidic inhibitor of neutral endopeptidase (NEP) capable of protecting atrial natriuretic peptide (ANP) from enzymatic degradation. In addition, CGS 26303 displays modest endothelin-converting enzyme (ECE) inhibitory activity in vitro. Unlike CGS 24592, a potent but selective NEP inhibitor, CGS 26303 significantly blocks endothelin-1 production in rats after exogenous administration of big ET-1 and reduces the mean arterial pressure in spontaneously hypertensive rats during chronic administration. These results suggest that CGS 26303 represents a new class of therapeutic agents with potential benefits for the treatment of cardiovascular and renal disorders.

Amino Acid Sequence↗
PubMed1994

Pharmacologic profile of CGS 24128, a potent, long-acting inhibitor of neutral endopeptidase 24.11.

We compared the pharmacologic profiles of thiorphan, a neutral endopeptidase (NEP) inhibitor which is cleared rapidly from the circulation, and CGS 24128, an inhibitor with a much longer half-life (t1/2). Thiorphan and CGS 24128 inhibited NEP in vitro with IC50 values of 5.0 +/- 0.2 and 4.3 +/- 0.2 nM, respectively. After administration at 10 mg/kg intravenously (i.v.), the concentrations of CGS 24128 in the plasma were > 500 nM for 4 h but plasma thiorphan was detectable for only 60 min. Thiorphan 3 mg/kg administered intraarterially (i.a.) increased plasma atrial natriuretic peptide immunoreactivity (ANPir) levels by 58 +/- 12% in rats administered exogenous ANP(99-126). This response lasted < 60 min, whereas the same dose of CGS 24128 produced an average increase of 191 +/- 19% in ANPir concentrations that persisted for 4 h. ANP-induced (1 microgram/kg i.v.) natriuresis was significantly potentiated in anesthetized rats pretreated (60 min) with a bolus of CGS 24128 10 mg/kg i.v. The change in urinary sodium excretion (UNaV) produced by ANP was 28.8 +/- 4.0 and 15.8 +/- 1.8 muEq/kg/min in CGS 24128- and vehicle-treated rats, respectively. ANP-induced natriuresis was also greater during continuous infusion of thiorphan (5 mg/kg bolus + 0.1 mg/kg/min i.v.; delta UNaV = 29.2 +/- 5.8 and 13.8 +/- 3.2 muEq/kg/min in drug- and vehicle-treated rats, respectively) but not when thiorphan was administered as a bolus (10 mg/kg i.v.) 60 min before the ANP challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Beneficial effects of combined thromboxane synthase inhibition/receptor blockade with CGS 22652 in a canine model of coronary thrombosis.

Various antiplatelet agents were examined for their effectiveness as adjuncts to thrombolytic therapy in a canine model of thrombin-induced coronary thrombosis. Aspirin (5 mg/kg i.v. bolus), CGS 15435A (thromboxane synthase inhibitor (TxSI), 0.1 mg/kg i.v. bolus +0.04 mg/kg per h) and BM 13.505 (thromboxane receptor antagonist (TxRA), 0.5 mg/kg i.v. bolus +0.2 mg/kg per h) administered concurrently with streptokinase (750,000 units/h) were examined for their effects on reperfusion and reocclusion, as were a combination therapy with CGS 15435A + BM 13.505 or the dual TxRA/TxSI inhibitor, CGS 22652 (1 mg/kg i.v. bolus +0.4 mg/kg per h). All dogs received heparin (150 U/kg bolus + 50 U/kg per h) throughout the experimental protocol. Survival analysis at reperfusion indicated that thrombolysis was significantly improved in dogs treated with CGS 15435A, BM 13.505, CGS 15435A+BM 13.505 or CGS 22652 over that of vehicle-treated animals. Both dual inhibitor groups and the BM 13.505 group were significantly different from aspirin. Aspirin-treated dogs were not different from vehicle. Otherwise, all treatments differed from the vehicle-treated group at reocclusion. Time and incidence of reocclusion for CGS 22652 was significantly improved over that of BM 13.505. Residual thrombus weight was significantly reduced in the CGS 22652-treated and BM 13.505 + CGS 15435A-treated animals. These findings demonstrate that streptokinase-induced thrombolysis is accompanied by TxA2/prostaglandin H2 synthesis and platelet activation and suggest a role for platelet activation during reocclusion following clot lysis. These studies also show it is possible to combine the beneficial effects of both a TxRA and TxSI into a single chemical entity, CGS 22652, which, when administered as adjunctive therapy to streptokinase, results in an apparent synergistic antithrombotic effect.

6-Ketoprostaglandin F1 alpha↗