Paul G. G. Gerlag

DIURETIC EFFICIENCY OF FUROSEMIDE DURING CONTINUOUS ADMINISTRATION VERSUS BOLUS INJECTION IN HEALTHY VOLUNTEERS

Furosemide delivery rate in the nephron has been reported to be one of the major determinants of diuretic response. In a randomized, crossover double‐blind study in eight healthy volunteers, we tested this hypothesis by comparing continuous intravenous infusion of furosemide (infusion rate, 4 mg/hr) during 8 hours after administration of an intravenous loading dose of 8 mg (total dose, 40 mg) with an intravenous bolus injection of 40 mg furosemide. During the study days subjects were rehydrated with isovolumetric amounts of fluid. Mean total urinary volume (Vur), sodium (UNa), potassium, and chloride excretion after 8 and 24 hours were significantly greater after treatment with continuous furosemide infusion when compared with bolus injection, whereas total urinary furosemide excretion showed no differences (Vur bolus versus Vur infusion, 5270 versus 6770 ml/8 hours; UNa bolus versus UNa infusion, 314 versus 430 mmol/8 hours; both p < 0.001). These findings strongly support the concept of the furosemide delivery rate into the nephron as a determinant of diuretic efficiency.

Diazoxide infusion in severe hypertension and hypertensive crisis.

Prompted by reports of hypotension with myocardial ischemia after bolus injection, we restudied the efficacy of diazoxide infusion (5 mg/kg, rate, 15 mg/min) in 35 hypertensive patients. In 20 patients with chronic hypertension, mean arterial pressure of 138 mm Hg was 110 (after 30 min) and 121 (after 8 hr). In 15 patients with hypertensive crisis, there was a fall from 159 to 126 (in 30 min) and 133 mm Hg (after 8 hr), similar to findings in 12 patients with hypertensive crisis treated with a 300‐mg bolus injection (159, 130, 140 mm Hg). In the latter, the maximal systolic blood pressure decrease was greater (56 mm Hg, reached in 4 min) than in the 15 patients with hypertensive crisis treated by slow infusion (38 mm Hg in 28 min). Thus, infusion of diazoxide causes a gradual decline of blood pressure and is, in contrast to current opinion, also an effective treatment in hypertensive crisis.

The effect of 2-mercaptoethanol on IgM and IgG antibody activity

The effect of reduction by 2-mercaptoethanol (2-ME) on antibody activity was studied in antisera with high and low IgG concentrations. Sera obtained from B10.LP nu/nu mice during a primary response against a rat PVG/c skin graft contained only 2-ME sensitive antibodies. However, when analyzed on sucrose gradients, IgG as well as IgM antibody activity was present. After raising the low serum IgG concentration (0.3-0.7 mg/ml) of these sera by addition of normal mouse serum (5.1 mg IgG/ml), 2-ME resistant antibodies became detectable. Hyperimmune C57BL6 anti PVG/c lymphocyte serum with a high IgG concentration (20.2 mg/ml) and antibody activity predominantly located in the IgG class was not affected by 2-ME treatment. These data show that IgG antibodies, although less susceptible to reduction than IgM antibodies, are not resistant to this treatment. At high IgG concentrations the proportion of inactivated IgG with specific antibody activity will be negligible but at low IgG concentrations the use of this method leads to serious underestimation of IgG antibody activity.

Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency

Ten haemodialysis (HD) patients with a median residual creatinine clearance (CLCR) of 1.9 ml·min−1·1.73 m−2 (range 0.6–5.3) were treated with oral furosemide (F) 2.0 g. Overall-efficiency (O-E, daily sodium excretion/total urinary F) and total-efficiency (Δ-E, increase in daily sodium excretion/total urinary F) were measured on the last 24 hours of each interdialysis interval. In addition, O-E was measured during the complete interdialysis interval in 10 HD patients with a median CLCR of 5.6 ml·min−1·1.73 m−2 (range 0.7–6.8) treated for 1 year with a fixed oral dose of F between 250–1000 mg (median 625 mg).In the short study the median O-E was 10.6 mmol·mg−1 (range 1.9–22.0) and Δ-E 6.2 mmol·mg−1 (range 1.3–11.2). The fractional excretion of sodium FENa was significantly increased from 9.6% (range 4.1–22.9) to 27% (range 14.6–56.2) during F treatment. A positive correlation was found between the basal FENa and Δ-E. In the long-term study median O-E was 6.4 mmol·mg−1. O-E and FENa showed no change over time although median RCC decreased from 5.6 to 1.9 ml·min−1·1.73 m−2 and median F excretion from 11.8 to 7.5 mg per day.It can be concluded that diuretic efficiency in haemodialysis patients is dependent on FENa and the state of hydration during the interdialysis interval.

Absorption of High Dose Furosemide (Frusemide) in Congestive Heart Failure

SummaryTo investigate the influence of the presence of oedema on the pharmacokinetics and pharmacodynamics of furosemide (frusemide) we selected 9 hospitalised patients (mean age 70.3 years, range 59 to 84 years) with severe congestive heart failure (NYHA III to IV) and an assessed amount of peripheral oedema of at least 5kg. In these patients the absorption of a single oral dose of furosemide 250mg was studied when their heart failure was decompensated and again, after intensive therapy, when it was clinically compensated. The mean (± SEM) weight loss after clinical treatment was 12.0 ± 2.2kg. Individual furosemide plasma concentration-time curves could be fitted adequately to a 1-compartment model with 1 first-order absorption and elimination process, in which absorption took place in 2 parts with different lag times. Comparing the decompensated state with the compensated state we did not find significant differences in pharmacodynamics, absorption half-life, elimination half-life, time to peak serum concentration, peak serum concentration itself and area under the plasma concentration-time curve. However, the relative amount of furosemide absorbed in the first fraction was significantly increased after compensation. We conclude that the presence of massive oedema in patients with congestive heart failure has a minor influence on the pharmacokinetics and pharmacodynamics of high dose oral furosemide.

Hyperacute rejection of skin allografts in the mouse. Sensitivity of ingrowing skin grafts to the action of alloantibody and rabbit complement.

The destructive action of alloantiserum and exogenous complement on ingrowing skin allografts was studied. B6AF1 recipients of a B10.D2 skin graft received a single intravenous injection of B6AF1 anti-B10.D2 serum (antiserum to H-2K.31) together with rabbit complement (RC) within the first 10 days after transplantation. Different models were used: recipients without immunosuppression, recipients treated with antilymphocyte serum, X-irradiation, or enhancing antibody. If the injection was given between day 5 and 10 after grafting, hyperacute rejection occurred in all cases. The rejection seemed to be most violent when the injection was given on days 7 or 8. Injections given on days 1, 2, or 3 after grafting could not induce hyperacuto-rejection, but resulted, on the contrary, in a prolongation of graft survival, probably due to immunological enhancement. Injections on day 4 produced patchy necrosis, but the grafts recovered and the residual tissue showed a prolonged survival. The results suggest that the presence of a functioning vascular network is a prerequisite for the occurrence of hyperacute rejection of skin allografts in the mouse.

Role of antiserum and complement in the acute antibody-mediated rejection of mouse skin allografts in strain combinations with increasing histoincompatibility.

Acute antibody-mediated rejection (AAR) of mouse skin allografts was studied in nine donor-recipient combinations with increasing histoincompatibility ranging from an H-Y to a complete H-2 plus on-H-2 disparity. AAR was induced by the injection of specific alloantiserum along with a heterologous complement on day 7 after grafting. Sera from rabbits, guinea pigs, and from a human volunteer were used as complement sources. The recipients were treated with antilymphocyte serum on days 0, 2, and 4 to postpone cell-mediated rejection. With increasing histoincompatibility the mean survival time of untreated grafts decreased, the in vitro cytotoxic activity of the alloantiserum rose, and AAR could be induced with lower amounts of antiserum. The higher efficiency of rabbit complement compared with guinea pig complement and human complement, that is known to exist in in vitro cytotoxicity, was also found in vivo. Rabbit complement could induce AAR in combination with relatively weak histoincompatibility (H-2K, H-2D, or non H-2 differences), where guinea pig complement and human complement were ineffective. All three complement species elicited AAR if there was a disparity for H-2D plus non-H2 H-2K plus non H-2, H-2, or H-2 plus non-H2. The rules for immunogenicity of the different histocompatibility loci as they have been described for cell-mediated graft destruction also apply to this humorally mediated rejection process.

Enhancement of skin grafts in the mouse. The combined use of specific and nonspecific immunosuppression.

Enhancement of skin grafts in mice by passively administered alloantiserum was examined in conjunction with the simultaneous use of other immunosuppressive regimens. It could be clearly shown that when a “weak” antilymphocyte serum (ALS) was used, a significant further prolongation of graft survival occurred over that obtained with the enhancing antiserum alone, and these two separate effects were synergistic. When a “strong” ALS was used, no synergistic effects were apparent unless the enhancing alloantiserum was given almost continuously. A similar, but less impressive synergism was seen when the enhancing alloantiserum and azathioprine were used together. Azathioprine, like ALS, presumably acts on T cells, whereas drugs directed against B cells, such as cyclophosphamide and prednisolone, failed to show any synergistic effect.