An open, prospective trial investigating the pharmacokinetics and safety, and the tolerability of escalating infusion rates of a 10% human normal immunoglobulin for intravenous infusion (IVIg), BT090, in patients with primary immunodeficiency disease.

BACKGROUND AND OBJECTIVES: Pharmacokinetics, safety and tolerability of escalating infusion rates of BT090, a 10% intravenous immunoglobulin (IVIg), were studied in patients with primary immunodeficiency disease. MATERIALS AND METHODS: In Part A, patients (n = 30) received 3 infusions of BT090 at their pretrial dose and dosing interval; the infusion rate of BT090 was increased from 0·3 to 1·4 to 2·0 ml/kg/h for each infusion in each patient initially at 30-min intervals. Pharmacokinetics was evaluated at the 3rd infusion (n = 24). At the 4th infusion, infusion rates were to be gradually escalated from 0·3 to 1·4 to 4·0 to a maximum of 8·0 ml/kg/h initially at 30-min intervals to establish the maximum tolerated infusion rate per patient. RESULTS: The pharmacokinetic characteristics and safety profile of BT090 were comparable with those of other IVIgs, including Intratect(®) . Escalation of infusion rates was well tolerated, allowing identification of individual patient's maximum tolerated infusion rate. At subsequent infusions, all patients tolerated their individually defined maximum infusion rate: 17 patients (68·0%) tolerated infusion rates of 6·0 or 8·0 ml/kg/h and four patients (16%) had maximum tolerated infusion rates of <4·0 ml/kg/h at subsequent infusions. Escalation of infusion rates shortened infusion time from a median of around 2·5 h to around 1·6 h. SAEs were reported in three patients, but none was related to BT090 treatment. CONCLUSIONS: Shortening infusion time may reduce overall healthcare spending, for example nursing time needed, and also minimize disruption of patients' daily routine, especially for those patients in work or school settings.

Pharmacokinetics of viral antibodies after administration of intravenous immunoglobulin in patients with chronic lymphocytic leukaemia or multiple myeloma.

OBJECTIVE: Intravenous immunoglobulin (IVIG) preparations are derived from human pooled plasma and should fulfil high standards of purity and viral safety. Introduction of additional purification steps, however, may result in modulation of the biological properties of immunoglobulins. Since cleavage of the Fab-fragment leads to a significant decrease in half-life, the latter provides information about the integrity of the immunoglobulin G (IgG) molecules. Therefore, a pharmacokinetic study of a novel preparation is required to determine safety and disposition in the target population. METHODS: Twenty-seven patients with chronic lymphocytic leukaemia (CLL) and 12 with multiple myeloma received intravenous infusions of IVIG containing antibodies against hepatitis B virus (anti-HBs; n= 15; 8960 IU), cytomegalovirus (anti-CMV; n = 9; 14,250 U) or varizella-zoster-virus (anti-VZV; n = 15; 6000 IU), respectively. Serum concentrations of viral antibodies were determined for 71 days during and after infusion. RESULTS: Maximum serum concentrations of anti-HBs, anti-CMV and anti-VZV were observed at about 4 h (median) after start of the infusion. Total body clearances came to 0.14 +/- 0.08 ml/min (anti-HBs), 0.10 +/- 0.02 ml/ min (anti-CMV) and 0.14 +/- 0.07 ml/min (anti-VZV). The terminal elimination half-lives were determined to be 25.34 +/- 8.34 days (anti-HBs), 24.66 7.28 days (anti-CMV) and 31.79 +/- 12.47 days (anti-VZV). Clinical chemistry parameters including C3- and C4-complement serum concentrations revealed no pathological changes, seroconversion for hepatitis B and C and HIV did not occur. CONCLUSIONS: The pharmacokinetic parameters of the IgG antibodies calculated after administration of the novel IVIG preparations to patients with CLL and multiple myeloma are in close agreement with data obtained from healthy volunteers and with values of native IgG, suggesting that the production process did not impair clinically relevant characteristics of the viral antibodies.

Acute and chronic haemodynamic and natriuretic effects of atriopeptin II in conscious rats.

The haemodynamic and natriuretic effects of an atrial natriuretic peptide were studied in conscious rats during acute and chronic administration of the peptide. Infusion of atriopeptin II (0.3 microgram/kg per min intravenously) for 60 min produced a fall in blood pressure and a rise in heart rate, accompanied by a significant decrease in renal and mesenteric blood flow. Despite the renal vasoconstriction, urinary sodium excretion increased markedly. These findings suggest that the hypotensive effect of atriopeptin II in conscious rats is not mediated by systemic vasodilatation, and that renal vasodilatation is not a prerequisite for the natriuretic action of this peptide. During infusion of atriopeptin II (24 micrograms/day) for 2 days, a small but persistent hypotensive effect was observed, which was accompanied by transient tachycardia. However, infusion of the same, or a higher (120 micrograms/day), dose of atriopeptin II for 4 days failed to produce any natriuretic effects. These results suggest that atrial natriuretic peptides are more important in acute than in chronic regulation of sodium excretion.

Is the natriuretic effect of atrial natriuretic factor in conscious rats mediated by renal vasodilatation?

Atrial natriuretic factors (ANF) have both vasorelaxant and natriuretic properties. It has been suggested that their effects on sodium excretion depend on renal vasodilatation. We studied the haemodynamic (ultrasound Doppler flow probes) effects of synthetic atriopeptin II at natriuretic doses in conscious rats. Intravenous injections of atriopeptin II induced a marked, dose-dependent increase in sodium excretion. This was accompanied by a slight reduction in blood pressure (BP) and a transient decrease in renal, mesenteric and aortic blood flow. In contrast, a selective renal vasodilator, CGP 22,979, induced a moderate increase in sodium excretion concomitantly with a rise in renal blood flow. Blood pressure and the other regional flows remained unchanged. These findings suggest that the natriuretic effect of CGP 22,979 is closely related to an increased renal blood flow. Conversely, the natriuresis induced by atriopeptin II is not accompanied by selective renal vasodilatation and appears to be due either to a tubular action or to changes in intrarenal haemodynamics.

Reduced activity of locus coeruleus neurons in hypertensive rats.

The effect of blood pressure on the neuronal activity of the locus coeruleus (LC) was investigated by means of electrophysiological techniques in rats anaesthetized with chloral hydrate. The mean neuronal discharge rate of noradrenergic neurons of the LC was reduced by 19% in spontaneously hypertensive rats (SHR) and by 25% in deoxycorticosterone acetate (DOCA)-salt hypertensive rats compared with their corresponding controls. The cellular activity of 27 out of 40 neurons was reversibly suppressed by acute, peripherally induced blood pressure increases in normotensive rats. Five neurons were reversibly activated and eight neurons were not affected. Conversely, acute decreases in blood pressure stimulated the neuronal activity of the LC in 10 out of 16 neurons. These findings support the hypothesis of the LC having a role in both short and long term regulation of blood pressure.

Reduced activity of locus coeruleus neurons in hypertensive rats.

The influence of blood pressure on locus coeruleus (LC) neuronal activity was investigated in chloral hydrate anesthetized rats. Mean spontaneous firing rate of LC neurons was reduced by 25% in deoxycorticosterone acetate (DOCA-salt) treated Sprague-Dawley rats and by 19% in spontaneously hypertensive rats (SHR) as compared to their corresponding control animals. In acute experiments performed on normotensive rats, peripherally induced blood pressure changes elicited reciprocal changes in cell firing of the majority of LC neurons. The findings suggest that LC may have a role in long-term regulation of blood pressure.

CGP 22979A, a renal vasodilator with natriuretic properties.

Renal vasodilation might be an interesting new antihypertensive principle. In the present study, the prodrug approach was adopted to synthesize a preferential renal vasodilator. A hydralazine-like compound, CGP 18137A (2-hydrazino-5-n-butyl-pyridine), was substituted with an N-acetyl-gamma-glutamyl residue. The resulting derivative, CGP 22979A [N-acetyl-L-glutamic acid-N[N2-(5-n-butyl-2-pyridyl)hydrazide]], was inactive in the isolated perfused mesenteric artery, whereas the parent compound induced a dose-dependent inhibition of vasoconstrictor stimuli. When administered i.v. to anesthetized rats in doses between 1.0 and 10.0 mg/kg, CGP 22979A increased renal blood flow significantly, by up to 31% without affecting blood pressure. A dose of 4.0 mg/kg lowered renal vascular resistance by 25% but did not alter total systemic, mesenteric and iliac vascular resistance. A dose of 10.0 mg/kg increased glomerular filtration rate by up to 42%. In conscious rats, the same dose increased sodium excretion by 200%. Because CGP 22979A induces renal vasodilation in rats and has a preferential action on the afferent arterioles, it might be a useful tool for studying the antihypertensive potential of renal vasodilation.

Glomerular albumin leakage and morphology after neutralization of polyanions. I. Albumin clearance and sieving coefficient in the isolated perfused rat kidney.

In order to decide whether foot process abnormalities in nephrotic states are the cause or the consequence of proteinuria, the polycation protamine has been applied to isolated perfused rat kidneys and functional parameters and morphology have been compared. With 110 micrograms/ml protamine the albumin clearance ratio increased from 2.0 +/- 0.7 x 10(-3) in controls to 14.8 +/- 6.9 x 10(-3) 10-20 min after application and even to 98.0 +/- 30.8 x 10(-3) after 50-80 min. Micropuncture samples collected from early proximal tubules with pressure control were used to calculate the sieving coefficient which correlated with albumin clearance ratios (controls: 1.8 +/- 1.0 x 10(-3); after 10-20 min: 11.8 +/- 6.4 x 10(-3); after 50-80 min: 52.0 +/- 8.5 x 10(-3). Glomerular filtration rate decreased in the early beginning from 1.1 +/- 0.2 ml x min-1 x g-1 kidney to 0.7 +/- 0.2 ml x min-1 x g-1 kidney, but remained constant throughout the whole experiment. Despite the markedly increased albuminuria there were no changes in glomerular foot process morphology with the protamine dose used.