Superiority of standard interferon-alpha2b compared to pegylated interferon-alpha2b (12 kDa) in a hemodialysis patient with chronic hepatitis C?

INTRODUCTION: Hepatitis C virus (HCV) infection represents an important problem for hemodialysis patients. Interferon-alpha (IFN-alpha) three times per week has been shown to clear HCV RNA in a substantial proportion of renal transplant candidates, and may thereby prevent the deleterious effect of immunosuppressive treatment on progression of liver disease in HCV-positive patients after renal transplantation. Data on the efficacy of the new pegylated interferons in hemodialysis patients are limited and general recommendations are absent. CASE: A 41-year-old Caucasian man infected with hepatitis C genotype 1b was admitted with a history of renal transplantation in 1990, and reintroduced hemodialysis in 1997 because of chronic rejection. Antiviral therapy with pegylated interferon-alpha2b (120 microg/oiw) and ribavirin (400 mg/tiw) was initiated. A virological and biochemical response with undetectable HCV-RNA was evident already after six weeks. Two weeks later, however, HCV-RNA became detectable again with 18.000 IU/ml. The treatment regimen was changed to standard-IFN-alpha2b (3 MU/tiw). Shortly thereafter, ribavirin had to be withdrawn because of severe anemia. After three weeks, hemoglobin level rebounded to values higher than 10 g/dl and a lower dose of ribavirin (200 mg/tiw) could be reintroduced. Virological and biochemical response occurred after switching to standard interferon-alpha2b within three months with good tolerance of antiviral combination treatment until the end of 48 weeks of therapy. The patient remained HCV-RNA-negative throughout follow-up of 36 weeks. ALT levels are still within normal limits and the patient is now waiting for a kidney transplantation. CONCLUSION: Considering the treatment course of this patient, IFN-alpha2b three times per week directly after hemodialysis seems to be superior to pegylated interferon-alpha2b once weekly in this case. The role of pegylated IFN-alpha2a for dialysis patients remains to be investigated.

Sympathetic nervous activity and the pressor effect of noradrenaline under chronic alpha-beta-adrenoceptor blockade with labetalol in hypertension.

In 14 patients with essential hypertension, the influence of the alpha- and beta-adrenoceptor blocking drug labetalol on blood pressure, heart rate, plasma renin, plasma noradrenaline and pressor effect of exogenous noradrenaline was investigated during long-term treatment. During the initial four weeks of treatment, labetalol at a dose of 400 mg/day showed a slight effect only on supine blood pressure, whereas upright blood pressure was already lowered effectively after the second week of treatment (p less than 0.01). An increase in the mean dose to 850 mg/day had an additional blood pressure-lowering effect (p less than 0.001), whereby a preferential decrease of the orthostatic blood pressure was no longer apparent. Further increase in the mean dose to 1,000 mg/day at the end of the 12th week did not have an additional blood pressure-lowering effect. Body weight, plasma renin and plasma noradrenaline remained unchanged on labetalol treatment in the lowest and the highest dose. There was, however, an increased pressor effect of exogenous noradrenaline, i.e. an alpha-adrenoceptor antagonistic effect of labetalol was not detectable under these conditions. The cause of the increased pressor effect was a reduced elimination of noradrenaline from plasma, which is probably the consequence of an inhibition of the uptake 1 process by labetalol. During long-term treatment with the doses administered, the blood pressure-lowering effect of labetalol appears essentially to be the expression of the beta-adrenoceptor blocking properties of the drug.

D-penicillamine in Wilson's disease presenting as acute liver failure with hemolysis.

Wilson's disease in a young woman presenting with an acute course is described. The clinical manifestations were fulminant hepatic failure associated with marked intravascular hemolysis. Immediate D-penicillamine and high-dose steroid therapy did not influence the course of the disease. Necropsy revealed an increased hepatic copper content and cirrhosis with extensive necrosis of the liver.

Contribution of the sympathetic nervous system to the hypertensive effect of a high sodium diet in stroke-prone spontaneously hypertensive rats.

In stroke-prone spontaneously hypertensive rats (SHRSP) plasma norepinephrine levels and vascular reactivity to norepinephrine are increased and intravascular volume is reduced during the developmental phase of hypertension. Since the accelerated rise in blood pressure following sodium-loading in SHRSP cannot be attributed to the volume-retaining properties of sodium, the effects of an increased dietary intake of sodium on biochemical parameters of sympathetic vascular tone were investigated. The following results were obtained. First, the increased reactivity of vascular smooth muscle was further augmented in sodium-treated SHRSP; the degree of supersensitivity was positively correlated to the plasma sodium concentration. After blockade of the neuronal uptake by 30 microM cocaine, no difference in vascular reactivity to norepinephrine was detected between SHRSP on a normal and SHRSP on a high-sodium diet. Second, the inactivation of norepinephrine by the neuronal uptake was impaired in rats on a high-sodium diet, the impairment being more pronounced in SHRSP than in Wistar-Kyoto (WKY) rats. This decreased inactivation could be expected to cause higher concentrations of the neurotransmitter at the receptor site if the transmitter release from the nerve ending remains constant. Third, the release of norepinephrine and epinephrine into the plasma was increased in sodium-loaded SHRSP but not in sodium-loaded WKY. Cold exposure exaggerates these differences between normotensive and hypertensive rats. These findings suggest that a high-sodium intake modifies the transmission of sympathetic impulses at the level of the nerve terminal in both WKY and SHRSP. In the normotensive rats, moderate impairment of norepinephrine inactivation, however, was balanced by an appropriate reduction in central sympathetic discharge following sodium-loading. In the hypertensive rats, the peripheral disturbance in norepinephrine inactivation due to sodium-loading was obviously not balanced by an adequate withdrawal of central sympathetic discharge. The resultant hemodynamic change was a further increase in the sympathetically mediated vasoconstriction, which is regarded as at least one of the main mechanisms of the sodium-dependent acceleration of hypertension in SHRSP.

Morphogenesis of hypertensive vascular lesions.

Accelerated hypertension is a convenient model for studying the pathomechanism of hypertensive vascular lesions. It has not been settled, however, whether such lesions are really equivalent to those developing slowly in the course of experimental hypertensive vascular disease. In the present study, early vascular lesions of accelerated hypertension have been compared with those of hypertensive vascular disease by using two complementary techniques: small-molecule plasma-protein label (Ferrlecit) and a macromolecular tracer protein (horse ferritin). Two kinds of vascular lesions have been distinguished. Non-destructive vascular lesions exhibit necrotic smooth-muscle cells with intracellular deposition of Ferrlecit-labelled plasma proteins and intact basement-membrane barrier to the macromolecular tracer. Destructive vascular lesions, in turn, are characterized by the breakdown of the basement-membrane barrier to the macromolecular tracer. Incipient destructive lesions are identified as dissecting microaneurysms initiated by small ruptures of the basement membrane framework. Both non-destructive vascular lesions and incipient destructive vascular lesions end in confluent medial destruction that precedes the formation of fibrinoid necrosis. The localization and morphology of vascular lesions is identical both in hypertensive vascular disease and in accelerated hypertension. Circumstantial evidence strongly suggests that non-destructive vascular lesions are caused by arterial contraction. Nevertheless, the possibility that non-destructive lesions are but abortive forms of destructive ones cannot be excluded.

Fluid and salt intake during the development of renal hypertension in rats.

1. In Sprague-Dawley rats, two-kidney, one-clip renal hypertension was induced, and the drinking behaviour as well as total fluid and sodium intake were studied before and for 16 days after the operation. 2. When water alone was offered as drinking fluid, the blood pressure reached values that were by about 20 mmHg higher than those in the rats which had free choice of drinking water or 2% saline. 3. In those rats which had water and 2% saline to drink, the total sodium and fluid intake rose transiently for three days, as compared with that of the sham-operated controls, and increased steeply starting from the 7th and 10th day, respectively. When a tighter stenosis of the renal artery was induced, the pressure rose more rapidly, and the total fluid and sodium intake increased continuously after the operation until the end of the experiment. 4. A positive correlation was demonstrable between the height of blood pressure and the total daily intake of fluid and sodium, respectively. 5. The relation between the total daily fluid and the total daily sodium intake followed a straight regression line. 6. The hypertensive rats which had a high total sodium intake responded to the withdrawal of the 2% saline solution, within 2 days, with increased water intake, decreased food intake, and loss of body weight, whereas the blood pressure remained high. 7. In the two-kidney, one-clip hypertension, no 'critical level of blood pressure' can be defined, beyond which the contralateral kidney starts to lose sodium.

Vasoconstriction and increased blood pressure in the development of accelerated vascular disease.

The pathogenesis of acute vascular lesions has been studied in two types of accelerated vascular disease. Firstly, vascular lesions were induced by a short-term (2 h) infusion of angiotensin II. Low doses of angiotensin II caused only a slight increase in blood pressure and non-destructive lesions. High doses caused a significant elevation of blood pressure and destructive vascular lesions. Secondly, in renovascular hypertension, renal vascular disease was induced by the removal of the stenosing clip from the renal artery. Incidence and severity of destructive vascular lesions were correlated with the calculated gradient between the pressure before and beyond the stenosis. Anaesthesia had a protective effect on the development of destructive vascular lesions in both models. Obviously, this effect is not related to a reduction of the systemic pressure, but rather to the suppression of abnormal vascular tone, characterized by focal constriction alternating with overdilation. Vasomotor changes, which cause a local overdilation, may be responsible for destructive vascular lesions even at normal to subnormal blood-pressure values. Destructive vascular lesions occur as a result of the exceeding of a critical wall tension. The necrosis of medial smooth-muscle cells in non-destructive lesions may be explained by an excessive contraction, which "surpasses" the metabolic capacity of the cells.

Modulation of sympathetic vascular tone by prostaglandins in corticosterone-induced hypertension in rats.

1. In corticosterone-induced hypertension in rats the activity of the peripheral sympathetic nervous system and its modulation by prostaglandins was studied. 2. Plasma concentrations of noradrenaline were reduced if compared with those in normotensive control rats. 3. The sensitivity of the isolated perfused hind-limb preparation to noradrenaline was enhanced before blood pressure rose and increased further with the development of hypertension. 4. Arachidonic acid, prostacyclin (prostaglandin I2), but not 6-keto-prostaglandin F1 alpha, reversed the supersensitivity to noradrenaline. 5. These results suggest that corticosterone induces a supersensitivity to noradrenaline by inhibiting the biosynthesis of prostaglandins. Changes in the sensitivity of the vascular smooth muscle may play a role in the development of glucocorticoid hypertension.

The pharmacological relevance of vital staining with neutral red.

The uptake of neutral red into the renin-containing juxtaglomerular granules does not inhibit the release of renin either in basal or in stimulated states of renin secretion. The vasodilating effect of neutral red may be due to a nonspecific binding to noradrenaline-receptors in the vascular smooth muscle cells.

Effects of beta-adrenergic blocking agents on peripheral vascular resistance.

The effects of the beta-adrenergic blocking agents propranolol, pindolol, atenolol, bunitrolol, and methypranol on the vascular resistance of isolated perfused hindlimbs of rats were investigated. At concentrations of 0.01 microgram/ml in the perfusate dl-propranolol and pindolol significantly increased vascular resistance by blockade of beta2-receptor mediated vasodilatation, whereas atenolol, bunitrolol and methypranol had no effect on peripheral resistance at this concentration. With increasing concentrations up to 10 microgram/ml all drugs, with the exception of atenolol, caused vasodilatation. We conclude that the specificity of beta-blocking agents can be established in the isolated perfused hindlimb vasculature of rats through its effect on vascular resistance. The lack of inhibition of vascular beta2-receptors at low concentrations of atenolol and also bunitrolol and methypranol show relative selectivity for beta1-receptors. The differential effects of beta-adrenergic agents on vascular resistance may have significance for the clinical use of the drugs.

Reversal of renal hypertension: effects on renin, salt and water balance.

The effect of removal of one renal artery stenosis on renal sodium and fluid excretion and on the activity of the renin-angiotensin system (RAS) has been investigated in three types of renal hypertension of rats. Blood pressure fell in all experimental models after declamping, independently of changes in urinary sodium and water excretion or plasma angiotensin II (ANG II). Plasma concentrations of ANG II did not rise in response to salt and fluid loss induced by declamping when the contralateral kidney had been removed or when it was depleted from renin. A high renin content of the declamped kidney prevented major salt and fluid loss, whereas renin depletion of this kidney was accompanied by an exaggerated natriuresis and diuresis. Besides this tubular modulation of renal salt and water handling by the local RAS, glomerular filtration rate could be reduced by a stimulated activity of this system in plasma, indicated by a close relationship between serum urea and plasma ANG II levels.

Mode of action of sodium nitroprusside on vascular smooth muscle.

1. Sodium nitroprusside is a potent relaxant of smooth muscles with a predominantly tonic response, e.g. rat aorta contracted by noradrenaline, angiotensin II, Phe2-Lys8-vasopressin, BaC1(2), or KC1, and guinea-pig tracheal smooth muscle contracted by carbachol. 2. Smooth muscle preparations from the splanchnic region and with varying degrees of phasic contractility are less sensitive and develop tachyphylaxis (portal vein, duodenum of the rat) or are unresponsive to sodium nitroprusside (vas deferens, uterus of the rat). 3. Cardiac auricles of the guinea pig are not affected by sodium nitroprusside in either frequency or amplitude or spontaneous contractions. 4. Sdium nitroprusside causes a parallel shift of the dose-response curve of rat aorta to noradrenaline to the right and reduces the maximum response. 5. The drug has no blocking or stimulant effect on alpha- or beta-adrenoceptors, respectively. 6. Sodium nitroprusside inhibits the contractile response of calcium-depleted depolarized rat aorta to extra-cellular calcium. Like verapamil, it inhibits the increment in 45calcium uptake of rabbit aorta elicited by K+. Sodium nitroprusside significantly reduced 45calcium binding by microsomes prepared from rabbit aorta. 7. Rabbit aorta was incubated with lanthanum chloride to prevent calcium influx; sodium nitroprusside reduced the maintained rapid contraction phase in response to noradrenaline which is believed to be based on the intracellular activation of calcium. 8. In rat aorta, cellular cAMP and ATP levels were not found to be affected by the drug. 9. Rabbit aorta, "skinned" by glycerination is unresponsive to sdoium nitroprusside. 10. It is concluded that sodium nitropruside acts on exictation-contraction coupling predominantly in tonic smooth muscle by interfering with both the influx and the intracellular activation of calcium.