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Biomedical subjects

F Dudley

Publications and source records attributed to F Dudley.

At least 19 recordsLinked to original sources
PubMed2006

Sustained virological response rates and durability of the response to interferon-based therapies in hepatitis C patients treated in the clinical setting.

International controlled trials have demonstrated increasing sustained virological response (SVR) rates to interferon-based therapies in hepatitis-C-treated patients. Response rates of 6-20% in the era of interferon monotherapy are compared with 42-82% with pegylated interferon plus ribavirin. The virological durability of the SVR is unknown and the optimal follow-up for these patients is unclear. The aim of our study was to determine SVR rates and the durability of the response to interferon-based therapies in the clinical setting. From our database of 1540 hepatitis C patients, 344 treatment courses of at least 12 weeks duration were identified, including interferon monotherapy (175 patients), interferon plus ribavirin (96 patients) and peginterferon plus ribavirin (73 patients). Interferon monotherapy was associated with an SVR rate of 5% in 103 genotype 1 patients and 25% in 72 genotype 2/3 patients. Response rates were higher (P < 0.001) with interferon plus ribavirin-41% in 34 genotype 1 patients and 73% in 62 genotype 2/3 patients-and with peginterferon plus ribavirin-47% in 47 genotype 1 patients and 79% in 26 genotype 2/3 patients. Of 147 patients with an SVR, 146 (>99%) remained hepatitis C virus PCR negative during a mean 2.3 years (range 0.3-10.3) of follow-up. In conclusion, with advances in therapies, we are achieving higher response rates in hepatitis C patients treated in the clinical setting. We can now expect an SVR in over half of the treated patients. Importantly, the response is durable and medium and long-term follow-up of these patients are of low yield and largely unnecessary.

Adolescent↗
PubMed1996

Smooth muscle-derived nitric oxide is elevated in isolated forearm veins in human alcoholic cirrhosis.

1. Cirrhosis is often complicated by disturbances in the systemic circulation. We have previously demonstrated decreased vascular responses to vasoconstrictors in forearm resistance arteries in subjects with alcoholic cirrhosis. In the current study we investigate the role of the potent endogenous vasodilator nitric oxide in the peripheral circulation of these patients. 2. Ten patients with alcoholic cirrhosis (Pugh grade A) and 10 age-matched control subjects were studied. The effect of blockade of nitric oxide synthesis was studied both in vivo in forearm resistance arteries using forearm venous occlusion plethysmography and in vitro in veins isolated from the forearm. The role of endothelium-derived nitric oxide was studied in vivo using the endothelium-dependent vasodilator acetylcholine. 3. Mean arterial pressure and forearm basal flow in vivo were similar in the two groups. The constrictor response (percentage decrease in forearm blood flow) to noradrenaline (100 ng/min) was 26% smaller in patients with cirrhosis (31.65 +/- 2.64%) than in control subjects (42.75 +/- 3.87%, P = 0.037). Constrictor responses to the nitric oxide synthase inhibitor NG-monomethyl-L-arginine were not different in the two groups. Dilator responses to acetylcholine were significantly attenuated in cirrhotic patients compared with control subjects. 4. To investigate the role of smooth muscle-derived nitric oxide in vitro, all veins were stripped of their endothelium. Responses to noradrenaline were significantly diminished in veins isolated from patients with cirrhosis compared with control subjects. Incubation with the nitric oxide synthase inhibitor N omega-nitro-L-arginine had no effect on responses to noradrenaline in veins from control subjects but significantly enhanced the maximal response to noradrenaline by 23.95% (range 3.77-100%, P = 0.043) in veins from patients with cirrhosis. 5. Responses to noradrenaline were attenuated in vivo in forearm resistance arteries in patients with alcoholic cirrhosis. This impairment was also apparent in forearm isolated veins, stripped of the endothelium. Our data exclude a major role for endothelium-derived nitric oxide but highlight a possible role for smooth muscle-derived nitric oxide.

Acetylcholine↗
PubMed1995

The effect of misoprostol on indomethacin-induced renal dysfunction in well-compensated cirrhosis.

BACKGROUND/AIMS: Indomethacin has been shown to have adverse effects on renal function in patients with well-compensated alcoholic cirrhosis. The aim of this study was to determine whether an oral prostaglandin E1 analogue, misoprostol, could prevent this indomethacin-induced renal dysfunction. METHODS: Six patients with well-compensated alcoholic cirrhosis were studied. Renal hemodynamics and tubular function were assessed by clearance techniques before and after an oral dose of (i) 50 mg of indomethacin alone (I50), and (ii) a combination of I50 and 200 micrograms of misoprostol. RESULTS: I50 produced a significant reduction in glomerular filtration rate, a fall in effective renal plasma flow and an increase in renal vascular resistance. Two hundred micrograms of misoprostol was able to abolish the deleterious renal effects of indomethacin totally, yielding an increase in glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance as well as an increase in urinary volume and urinary sodium excretion. These beneficial effects were maximal in the hour immediately following medication, but were only transient, and this may be a limiting factor in its clinical use. CONCLUSIONS: If the beneficial renal effects of misoprostol could be confirmed after chronic administration, then the vasodilatory, natriuretic and diuretic potential of 200 micrograms of misoprostol could be of potential therapeutic value in patients with well-compensated alcoholic cirrhosis who require non-steroidal anti-inflammatory drug therapy.

Administration, Oral↗
PubMed1995

The dose-dependent effect of misoprostol on indomethacin-induced renal dysfunction in well compensated cirrhosis.

Misoprostol (200 micrograms) has been shown to acutely counteract the indomethacin-induced renal dysfunction in well compensated cirrhotic patients. The aim of this study was to determine if the prophylactic value of misoprostol was dose-dependent. Parameters of renal hemodynamics and tubular sodium and water handling were assessed by clearance techniques in 26 well compensated cirrhotic patients before and after an oral combination of 50 mg of indomethacin and various doses of misoprostol. The 200-micrograms dose was able to totally abolish the deleterious renal effects of indomethacin, whereas the 800-micrograms dose resulted in significant worsening of renal hemodynamics and sodium retention. These changes were maximal in the hour immediately after medications and slowly returned toward base-line levels thereafter. These results suggest that the renal protective effects of misoprostol is dose-dependent. However, until this apparent ability of 200 micrograms of misoprostol to prevent the adverse effects of indomethacin on renal function is confirmed with chronic frequent dosing, it would be prudent to avoid nonsteroidal anti-inflammatory therapy in patients with cirrhosis.

Diuresis↗
PubMed1994

Renal response to a saline load in well-compensated alcoholic cirrhosis.

A total of 29 patients with well-compensated alcoholic cirrhosis and 9 healthy control subjects of similar age and sex were studied to assess their response to a challenge of 2 L of normal saline infused over a 1 hr period. Patients with cirrhosis had an adequate effective arterial blood volume in the basal state as assessed by neurohumoral markers of vascular filling. They also had a lower renal vascular resistance (p = 0.048) and a higher glomerular filtration rate (p = 0.014) than the controls, indicating the presence of renal vasodilation. Both groups were in sodium balance, but the patients with cirrhosis had a higher filtered load of sodium, an increased proximal tubular reabsorption of sodium (p = 0.015) and a decreased fractional excretion of sodium (p < 0.001). The administration of a saline load was not accompanied by any significant changes in the renal circulation in the patients with cirrhosis. They were unable to suppress their proximal tubular reabsorption of sodium to the same extent as the controls (p = 0.012), so by the fourth hour a significant difference in the rate of urinary excretion of sodium was evident. In the patients with cirrhosis, glomerular filtration rate before and after the saline load correlated significantly with indocyanine green extraction (r = 0.65; p = 0.002), whereas the tubular handling of sodium was dependent on antipyrine clearance (r = 0.80; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Dose-dependent effects of oral misoprostol on renal function in alcoholic cirrhosis.

BACKGROUND/AIMS: Prostaglandins are important modulators of renal physiology, particularly when the effective circulatory volume is decreased. The aim of this study was to determine the dose-dependent effects of an oral prostaglandin E1 analogue, misoprostol, on renal function in patients with well-compensated alcoholic cirrhosis. METHODS: Renal hemodynamics and tubular function were assessed by clearance techniques, before and after 100-microgram, 200-microgram, 400-microgram, or 800-microgram oral doses of misoprostol. RESULTS: Overall, the results indicate that low-dose misoprostol is vasodilatory, natriuretic, and diuretic whereas high-dose misoprostol increases renal vascular tone and inhibits sodium and water excretion. The 200-microgram dose produced a transient but significant increase in the glomerular filtration rate and effective renal plasma flow and a decrease in renal vascular resistance. Urinary volume and urinary sodium excretion increased and urinary osmolality decreased. CONCLUSIONS: The results suggest that, in patients with well-compensated cirrhosis, the renal effects of misoprostol are determined by a bell-shaped dose-response curve. The renal vasodilatory, natriuretic, and diuretic potential of 200-micrograms of misoprostol suggests that it may be of therapeutic value in patients with cirrhosis.

Administration, Oral↗
PubMed1994

Nifedipine: its effects on renal hemodynamics and sodium homeostasis in well-compensated alcoholic cirrhosis.

Following the administration of 10 mg of nifedipine to 11 patients with well-compensated alcoholic cirrhosis, there was a significant fall in mean arterial blood pressure, accompanied by an increase in heart rate, presumably due to a significant decrease in systemic vascular resistance. Despite the fall in renal perfusion pressure, there was an increase in the effective renal plasma flow and a significant decrease in renal vascular resistance. The glomerular filtration rate was preserved, suggesting that the decrease in renal vascular resistance was due to a preferential decrease in afferent arteriolar tone. There were no significant changes in the filtered sodium load or the tubular reabsorption of sodium and urinary sodium, and urinary volume did not alter significantly. Although the current study indicates that nifedipine can improve the renal circulation in patients with cirrhosis, the significant effects on the systemic circulation suggest that its potential to reverse the intense renal vasoconstriction that can complicate the clinical course of advanced liver disease is unlikely to be of value in the treatment of the hepatorenal syndrome.

Aged↗
PubMed1993

Impaired reactivity of the peripheral vasculature to pressor agents in alcoholic cirrhosis.

BACKGROUND: Studies of the in vivo vascular reactivity of the peripheral circulation to pressor agents in cirrhosis have produced conflicting results, possibly because of changes in mean arterial pressure that make it difficult to clearly separate peripheral and central effects. The aim of the present study was to assess the reactivity of the forearm circulation to pressor agents in vivo without activating central control systems. METHODS: Forearm blood flow was measured by venous occlusion strain gauge plethysmography in the basal state and during the infusion of subpressor doses of norepinephrine and angiotensin II into the brachial artery in 10 male patients with well-compensated alcoholic cirrhosis and 10 male age-matched controls. Plasma renin activity and aldosterone and angiotensin II concentrations were assayed. Forearm and systemic sympathetic nervous system activity was estimated using a norepinephrine spillover technique. RESULTS: Basal forearm blood flow, renin angiotensin aldosterone system activity, and forearm sympathetic nervous system activity were similar in both the control and cirrhotic groups. The cirrhotic patients showed an impaired response to both norepinephrine and angiotensin II. CONCLUSIONS: There is impaired reactivity of the peripheral vasculature to pressor agents in cirrhosis, indicating that the control of vascular tone is disturbed even in well-compensated cirrhosis.

Adult↗
PubMed1993

Indomethacin-induced renal dysfunction in patients with well-compensated cirrhosis.

BACKGROUND: Patients with cirrhosis and ascites are especially sensitive to the adverse renal effects of indomethacin-induced inhibition of prostaglandin synthesis. The aim of this study was to determine whether indomethacin affects renal function in patients with well-compensated cirrhosis. METHODS: Clearance techniques were used to assess renal hemodynamics and sodium and water homeostasis. RESULTS: The oral administration of 50 mg of indomethacin to well-compensated patients with alcoholic cirrhosis was followed by a significant decrease in glomerular filtration rate (GFR) and effective renal plasma flow because of a preferential increase in afferent arteriolar tone. Indomethacin was both antidiuretic and antinatriuretic due principally to decreased free water clearance and increased proximal tubular reabsorption of sodium. The acute changes in renal function were not sustained. Patients with a high basal GFR were particularly sensitive to the adverse renal effects of indomethacin. CONCLUSIONS: This study indicates that in patients with well-compensated cirrhosis renal prostaglandins are functionally active and may contribute to the pathogenesis of glomerular hyperfiltration. Nonsteroidal anti-inflammatory drugs should be used with caution in all patients with cirrhosis.

6-Ketoprostaglandin F1 alpha↗
PubMed1993

Glomerular hyperfiltration in patients with well-compensated alcoholic cirrhosis.

BACKGROUND: Peripheral and splanchnic arteriolar tone is often decreased in patients with cirrhosis. The responsible circulating vasodilator(s) would be expected to also lower renal vascular resistance. To examine this possibility we have undertaken a hemodynamic study of the renal circulation in patients with stable, well characterized, compensated cirrhosis and in healthy controls of similar age and sex. METHODS: Clearance techniques were used to assess splanchnic and renal hemodynamics and hepatocellular function. RESULTS: Renal vascular resistance was significantly reduced in the cirrhotic patients (P = 0.048) and was accompanied by a significant (P = 0.014) and proportional (r = -0.45; P = 0.016) increase in glomerular filtration rate. The hepatic extraction of indocyanine green, a measure of functional intrahepatic portasystemic shunts, was the only independent predictor of glomerular filtration rate (r = -0.65; P = 0.002). CONCLUSIONS: The results support the hypothesis that, in patients with cirrhosis, the presence of portasystemic shunts results in an increased delivery of endogenous vasodilator(s) into the systemic circulation where their principal action on the renal circulation is to preferentially decrease afferent arteriolar tone. The resultant glomerular hyperfiltration may contribute to the pathogenesis of cirrhotic glomerulosclerosis.

Adult↗
PubMed1992

Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis.

OBJECTIVE: To study disturbances in sympathetic nervous system function in patients with alcoholic cirrhosis and the effect of clonidine on such disturbances. DESIGN: Cross-sectional physiologic and neurochemical evaluation of patients with cirrhosis and of healthy controls; an uncontrolled trial of intravenous clonidine in the cirrhotic patients. PATIENTS: Forty-four hospitalized patients with biopsy-proven alcoholic cirrhosis and 31 healthy controls. INTERVENTIONS: Intravenous clonidine. MAIN OUTCOME MEASURES: Radiotracer-derived measures of norepinephrine release to plasma, central hemodynamics, wedge hepatic vein pressure, and measures of renal function. MAIN RESULTS: In patients with cirrhosis, clonidine reduced previously elevated norepinephrine overflow rates for the whole body, kidneys, and hepatomesenteric circulation. This sympathetic inhibition was accompanied by the following potentially clinically beneficial effects: the lowering of renal vascular resistance (median reduction, 24%; 95% CI, 14% to 31%), the elevation of glomerular filtration rate (median increase, 27%; CI, 14% to 39%), and the reduction of portal venous pressure (median reduction, 25%; CI, 18% to 32%). The norepinephrine and hemodynamic responses to graded clonidine dosing (1, 2, and 3 micrograms/kg body weight intravenously) indicated that the sympathetic outflow to the hepatomesenteric circulation was more sensitive to pharmacologic suppression with clonidine than was the sympathetic outflow to the systemic circulation. CONCLUSIONS: The sympathetic nerves to the kidneys, heart, and hepatomesenteric circulation are stimulated in patients with cirrhosis. Clonidine inhibits these activated sympathetic outflows differentially, which could possibly provide a basis for the selective pharmacologic treatment of portal hypertension in patients with cirrhosis.

Adult↗
PubMed1991

Surgical treatment of biliary stricture with portal hypertension using veno-venous bypass.

The surgical treatment of benign bile duct stricture with portal hypertension may be hazardous and, in some cases, involve a 2-stage procedure. An initial porta-systemic shunt is performed followed by surgical correction of the stricture at a second operation. The use of veno-venous bypass, as described, provides a temporary porta-systemic shunt, allowing a 1-stage repair of the stricture to be carried out.

Biliary Tract↗
PubMed1985

Total and renal sympathetic nervous system activity in alcoholic cirrhosis.

Basal sympathetic nervous system activity was assessed in 8 unmedicated patients with alcoholic cirrhosis using a previously developed radiotracer method for measuring total and renal noradrenaline release to, and clearance from, plasma. Compared to the control group total noradrenaline clearance was significantly increased in the patients with advanced alcoholic cirrhosis (Pugh grade C) [1.89 +/- 0.13 vs 1.51 +/- 0.11 l/min, P less than 0.05) indicating that endogenous plasma noradrenaline levels underestimate total sympathetic nervous system activity in these patients. Renal noradrenaline clearance was similar to controls independent of the severity of the liver disease. Both total and renal noradrenaline release were significantly increased in the patients with cirrhosis. The ratio of renal to total noradrenaline release was similar in cirrhotic (26 +/- 7%) and control (23 +/- 5%) groups. Increased arterial plasma adrenaline levels, indicative of adrenal medullary stimulation, were also evident in the patients with cirrhosis and correlated significantly with total noradrenaline spillover (r = 0.732, P less than 0.05). These results strongly suggest that in patients with cirrhosis, rather than a preferential increase in renal sympathetic tone, the increase is part of a pattern of generalized sympathoadrenomedullary activation. Although renal renin secretion was significantly increased in the cirrhotic group no correlation with renal noradrenaline release was seen (r = 0.199), raising the possibility that in cirrhosis renal sympathetic tone is not a major determinant of renal renin secretion. Finally, renal noradrenaline release did not correlate with renal blood or plasma flow but an influence of the sympathetic nervous system on renal function was suggested by the correlation observed between total noradrenaline spillover and impaired salt (r = -0.683, P less than 0.05) and water excretion (r = -0.702, P less than 0.05) demonstrated in the cirrhotic patients.

Adrenal Medulla↗
PubMed1985

Morbidity and mortality after peritoneovenous shunt surgery for refractory ascites.

A prospective analysis of the morbidity and mortality after peritoneovenous shunting was carried out in 25 patients who had a total of 27 shunts for refractory ascites. Major complications were limited to the patients in whom ascites was secondary to hepatic rather than peritoneal disease. Immediate postoperative complications followed 17 out of the 23 shunts carried out in patients with liver disease and included septicaemia (two), profound hypotension (two), pulmonary oedema (one), and clinically evident disseminated intravascular coagulation (14). Long term morbidity was again limited to the patients with liver disease and included chronic shunt infection (two) and major venous thrombosis (two). Shunt associated mortality was only seen in the patients with liver disease. Despite late shunt blockage in five long term survivors with alcoholic liver disease fluid retention was easily controlled by simple medical means probably because of improved liver function associated with abstinence from alcohol. It is concluded that: (1) patients with hepatic and malignant ascites respond differently to the insertion of a peritoneovenous shunt; (2) Shunt patency should be monitored regularly in patients with liver disease and, because of the potential for septic and thrombotic complications, if blocked the shunt should be removed and; (3) because of the morbidity and mortality of peritoneovenous shunt surgery in patients with liver disease and refractory ascites, an alternative mode of therapy, such as repeated ultrafiltration and reinfusion of ascitic fluid, may be a more effective initial therapeutic approach especially in patients in whom there is a reversible element to their underlying liver disease.

Ascites↗