Examination of the biological safety of a drug derived from mammalian organs.

In order to assess the safety of a biological drug, a variety of factors have to be examined and then brought into an overall context considering the specific aspects of each individual product. Quoting Trasylol, the aprotinin (CAS 9087-70-1) drug extracted from bovine lungs as an example for such an approach, the complete procedure is discussed. The rationale of a safety concept, its implementation including safety related validation studies, and the combinatorial evaluation of results from these validations with underlying specificities for manufacture allow for an overall safety assessment. Validation of the removal/inactivation capacity of the manufacturing process for bovine spongiform encephalopathy (BSE) and various viruses showed high reduction potentials. These results constitute the cornerstone for the conclusion that Trasylol is safe with regard to BSE and viruses.

Treatment of chronic relapsing inflammatory demyelinating polyneuropathy by cyclosporin A and plasma exchange. A case report.

A patient with chronic relapsing inflammatory demyelinating polyneuropathy was successfully treated with plasma exchanges and cyclosporin A (CsA). Dynamometric measurements of hand force during the time of CsA treatment showed a highly significant correlation between hand force and CsA blood levels. The largest influence of CsA on hand force occurred 11-13 days after CsA uptake.

Model for individual substitution of immunoglobulins after membrane plasma separation.

Patients who undergo extensive plasma exchanges using albumin replacement may be more susceptible to infection because they develop significant hypogammaglobulinemia. Substitution of IgG in these patients could be beneficial. A model to calculate the individual amount of IgG required is described. The course of IgG during chronic intermittent membrane plasma separation (MPS) therapy was simulated using an one-pool model. Three modes of substitution were considered for their efficacy: infusion after MPS infusion after discarding an equivalent plasma quantity after termination of MPS, and plasma exchange at the end of MPS against an IgG solution. Mode B was shown to be most economical and was subsequently used to check the validity of the substitution model in a prospective test. The difference between predicted and measured IgG levels was 5% both for simulations from one MPS to the next and for the long-term prediction. The data prove that replacement of IgG after plasma separation is practicable. The substitution model allows to fix in advance any plasma limit value for indication and target of the substitution therapy. Thus it permits to give therapeutic recommendations for individual IgG substitution therapy of secondary antibody deficiency after MPS.

Aluminum load in chronic intermittent plasma exchange.

Aluminum (Al) loading due to administration of human albumin (HA) solutions was studied in 2 patients with stable renal function who underwent plasma exchange once (patient A) and twice (patient B) per week for treatment of hyperviscosity syndrome. Al was determined by Zeeman-AAS in plasma before, during and after treatment, also in bone of one patient and in various preparations of HA from different manufacturers. In addition, the net Al uptake (difference between total Al influx and efflux) and the 24th urinary excretion between 2 exchanges were determined. The electrolyte solution used for dilution had no detectable Al, while HA contained between 15 and 1900 micrograms Al/l. Increase of Al in plasma after treatment was clearly related to Al content of the HA used. When the patients received substitution solutions based on inadvertently highly Al contaminated 20% HA (1419 micrograms/l), the average net uptake was 2265 in patient A and 2049 micrograms in patient B and plasma Al rose from 8.4 respectively 18.0 before to 69.2 and 86.5 micrograms/l after treatment. By using medium Al contaminated HA (574 micrograms/l), the net uptake was 742 (pat. A) and 819 micrograms (pat.B), and there was an elevation of plasma Al from 5.1 respectively 18.2 to 34.2 and 39.8 micrograms/l. Following a net uptake of 870 micrograms patient A excreted 668 micrograms Al until the next treatment (23% positive balance). Treating patient A with a low Al HA (47 micrograms/l), there was a slight increase of plasma Al from 10.8 to 16.2 micrograms/l, the net Al uptake was negligible (less than 10 micrograms), and the weekly Al balance was negative. After 10 months of plasma exchange therapy (patient A) there was no increase of Al in bone (6.4 micrograms/g). We conclude, that the use of HA with a low Al contamination is recommended for all patients receiving this therapy during chronic intermittent plasma exchange or for other indications, especially in cases with impaired renal function.

Nomograms for the prediction of patient's plasma volume in plasma exchange therapy from height, weight, and hematocrit.

The knowledge of plasma volume (PV) is a basic requirement for the standardization of plasma exchange therapy. PV has to be determined by calculation, as the measurement of PV before every plasma exchange is too cost- and time consuming. A known correlation with measured values results from calculation of plasma volume by means of patient's height and weight. But the present equations are only reliable at normal hematocrit. For this reason we modified the Retzlaff-equations and compared the validity of plasma volume predictions, calculated by these and own equations, with plasma volume measured by the 51Cr-method in 59 patients with pathological hematocrit. The correlation coefficient was 0.82 for men and 0.81 for women (2 0.001) with the modified Retzlaff-equations. On the average the relative error was -1.5% for all and 2.8% for fat and thin men. No significant improvement of accuracy was achieved with other equations. Thus, plasma volume can accurately be calculated from height, weight, and hematocrit with our modified Retzlaff-equations in patients with pathological hematocrit, even if they are very fat or thin. Nomograms for men and women were constructed in order to facilitate the calculation.

Alteration of cellular calcium metabolism as primary cause of hypertension.

In the pathogenesis of hypertension, the importance of intracellular calcium is increasing. Clinical and experimental studies of essential hypertension indicate a pathological increase of intracellular Ca2+ in this disease. In the past, changes in cellular Na+ and its transport mechanisms were considered the triggering factors and Na+-Ca2+ exchange was attributed a decisive influence on intracellular homeostasis. Recently, a reduced Ca2+-binding capacity of the cellular membrane was observed in hypertension, which could have been due to a defect of the Ca2+-ATPase or its control. It is therefore necessary to establish the hypothesis that changes in the cellular Ca2+ metabolism associated with an increase in the intracellular Ca2+ concentration may be the primary cause of hypertension. Disorders of Na+ transport can also be traced to the increase in intracellular Ca2+ and were thus a consequence but not the cause of the increased intracellular Ca2+ concentration.

[Successful treatment of kappa light chain nephropathy using membrane plasma separation]. / Erfolgreiche Behandlung der Kappa-Leichtketten-Nephropathie durch Membranplasmaseparation (MPS).

Often the diagnosis "light chain nephropathy" is not made before renal failure has developed. In the past these patients had a poor prognosis. Special features of this disease and improvement of renal function by plasma exchange therapy are shown in a case report. A 51-year-old man admitted to hospital with renal failure, proteinuria and hypercalcaemia was treated by Ca-free dialysis and membrane plasma separation (MPS). Renal biopsy studied by light and electron microscopy showed mainly tubular protein casts. It is assumed that this nephropathy is caused by a direct toxic effect of the kappa light chains on function and structure of tubuli. Proteinuria was markedly lowered and renal failure was made partly reversible by prompt and effective MPS. Thus, MPS may improve the prognosis of this stage of disease.

Membrane plasma separation: complications and monitoring.

During the last 3 years, 306 membrane plasma separations (MPS) were performed on 40 patients. Activated partial thromboplastin time (APTT), oncotic pressure (OP), blood count, free hemoglobin, prothrombin time, fibrinogen, and factors II, V, VII, VIII, IX, X, XI, and XIII were determined. The complication rate was evaluated. Mild complications were observed in 4.2% of the cases (extracorporeal coagulation 1.5%, hypotensive episodes 2%, allergic reactions 0.7%). Severe complications were not observed. A flexible heparinization schedule dependent on the APTT values is necessary. In general, 4,500-7,000 IU/MPS is required. The serum OP is maintained within the normal range using a 3-6% human albumin solution to prevent circulatory complications. A marked loss of fibrinogen occurs with short intervals between successive treatments. The remaining coagulation factors are reduced by an average of 32% and the prothrombin time by 28%. Control of the heparinization and OP is essential for monitoring plasma exchange therapy.

Improvement of uremic neuropathy and hypogeusia by dialysate zinc supplementation: a double-blind study.

A reduction in the plasma zinc concentration is a well-recognized complication of hemodialysis. A positive clinical response to zinc therapy under controlled conditions is the most reliable criterion of zinc deficiency. Zinc therapy using a nonproprietary zinc dialysate was evaluated in 12 dialysis patients with proven hypogeusia and polyneuropathy, in a randomized double-blind crossover comparison (preliminary phase, 4 weeks; placebo phase, 12 weeks; initial phase, 12 weeks; final phase, 6 weeks; post phase, 4 weeks). The dosage was related to the zinc plasma and erythrocyte levels, measured weekly. Nerve conduction velocity (NCV) and taste-testing were used to evaluate the effect of treatment at the end of the placebo and therapy phases. There was significant reduction in the recognition and determination threshold level for each of the four qualities of taste. The NCV improved significantly. The plasma zinc level could be elevated in all patients to the desired concentration, using individualized supplementation of dialysate with zinc. The erythrocyte zinc level remained constant, at double the normal value. The plasma zinc concentration fell back to the initial level 6 weeks after conclusion of therapy. We conclude that (1) zinc substitution may provide a specific therapy for uremic polyneuropathy, (2) the observed hypogeusia results from zinc deficiency, (3) long-term therapy is necessary to obtain a constant normal plasma zinc concentration, (4) zinc substitution by dialysate is a suitable and nonstressful method of administration.

Viscosity adaption for an automated micromethod of flame atomic absorption spectrometry, and intracellular trace-element analysis after pressure decomposition: zinc determination in plasma and erythrocytes.

We measured zinc in the plasma of 50 normal persons, and in erythrocytes of six, by an automated micromethod of atomic absorption spectrometry. Using a rotation viscometer, we measured the viscosity and flow behavior of plasma, undiluted and equi-volume diluted (with water), from 12 patients, and, for comparison, of two- to 20-fold dilutions of an 870 mL/L glycerol solution. Erythrocytes were washed three times, lyophilized, and wet-ashed in a pressure decomposition device. The mean viscosity of equi-volume diluted plasma is about the same as that of the glycerol solution diluted 7.5-fold. The observed concentration of zinc in normal plasma was 13.8 (SD 1.9) mumol/L, with intra-assay CV (n = 30) of 2%, day-to-day CV (n = 22) 3.8%, and accuracy (measurement of an aqueous std.) 2.5%. The mean normal value for erythrocyte zinc was 34.7 micrograms/g, with intra-assay CV (n = 8) 5%, day-to-day CV (n = 6) 5.9%, and accuracy 4.6%. Our results compare well with those by neutron activation analysis, the differences in values being 3% for plasma, 1% for erythrocytes.

Haemodiafiltration.

Using haemodiafiltration--a combination of haemodialysis and haemofiltration--an increased clearance rate for middle and small molecules can be obtained compared to the single technique alone. Low molecular weight substances are removed mainly by diffusion, and middle molecules predominantly by convection. Using currently available equipment the duration of therapy can thus be reduced by at least one-third, compared with haemodialysis, without deterioration in the patient's general condition. The withdrawal of large volumes of fluid is markedly better tolerated by the patient than with other short-time blood purification procedures. With the aid of haemodiafiltration both molecular groups can be diminished independently of each other according to individual demand, thereby leading to optimization of dialysis therapy.