Preparation of sustained release co-extrudates by hot-melt extrusion and mathematical modelling of in vitro/in vivo drug release profiles.

Aim of this work was to develop a cylindrical co-extrudate characterised by an in vivo sustained release profile by means of a hot-melt extrusion process. Co-extrudate was made up of two concentric extruded matrices: an inner one having a hydrophilic character, based on polyethylene glycol, and an outer one with lipophilic character, based on microcrystalline wax. Both segments contained theophylline as a model drug. A screening between several devices differing for dimensions (diameter and length) and relative proportions of the inner and outer part was carried out on the basis of their in vitro drug release and the release mechanism was studied by means of a mathematical model. The co-extrudate exhibiting the desired sustained release was selected for in vivo bioavailability studies. In vivo studies confirmed the achievement of the purpose of the research, demonstrating the desired release of theophylline on four healthy volunteers. Accordingly, hot-melt extrusion process is a viable method to produce in a single step co-extrudates showing a sustained release. In addition, the developed mathematical model proved to be a reliable descriptor of the both in vitro and in vivo experimental data.

[The hemodialysed patient and his/her family caregiver. Comparison of perceptions of the chronic illness]. / Il paziente emodializzato e il caregiver familiare. Percezioni a confronto sulla malattia cronica.

BACKGROUND: According to health psychology, the family caregiver (fc), i.e. the person who takes care of a hemodialysed patient, plays a pivotal role in coping with dialysis. This study explored and compared the lifestyle and the main needs of a cohort of hemodialysis patients, with reduced personal autonomy, to their fc, evaluating some psychological functional parameters, such as the perception of familial and social support, the psychological quality of life, the disability due to chronic illness, and the communication style. METHODS: An anonymous multiple versions questionnaire, administered according to the caregiver's family relationship, was given for self assessment to 54 couples of patients and related fc (spouse, son/daughter and brother/sister), mean age 66 and 60, respectively; mean dialytic patients' age: 8 years and 6 months. The questionnaire consisted of three different sections, demographics, renal disease and psychological evaluation, with 4 standard scales (Social Support Satisfaction, Marital Communication, Psychological General Well-Being Index and Evaluation of Needs). A multivariate variance analysis (MANOVA) was subsequently performed. RESULTS: Women have a higher perception of their lifestyle change after dialysis, and, in general, patients communicate more easily with their fc than vice versa. Communication problems are more common in patients with a recent diagnosis. Patients and fc mostly need a better dialogue with their nephrologists and urge some psychological help. CONCLUSIONS: The quality of the relationship between physicians, patients and their families is a key element in the process of healing.

Prescription and assessment of tidal peritoneal dialysis delivery with a specific equilibration test.

OBJECTIVE: To propose a simplified equilibration test specific for tidal peritoneal dialysis (TPD) that will overcome the inconveniences of the measurement of TPD peritoneal solute clearances through whole dialysate collection. This will enable the prediction of peritoneal creatinine and urea clearances, the suitability of patients for TPD, and routine assessment of TPD delivery. DESIGN: In a prospective study, patients had a standardized TPD run, and dialysate-to-plasma (D/P) ratios for creatinine and urea were calculated at various TPD and peritoneal equilibration test (PET) time points and on total TPD dialysate. Solute clearances were estimated and measured, and correlation coefficients were obtained among all these variables. SETTING: Dialysis unit of a pediatric nephrology department and patients' homes. PATIENTS: Eleven pediatric patients with end-stage renal disease in stable clinical conditions treated with TPD. INTERVENTIONS: Dialysate and blood sample collections. MAIN OUTCOME MEASURES: D/P ratios for creatinine and urea at the fifth and seventh TPD exchanges, at 15-, 30-, 60-, and 120-minute PET times, and on total TPD dialysate and TPD peritoneal creatinine and urea clearances. RESULTS: Correlation coefficients between PET-derived and total TPD dialysate-derived D/P ratios, and those between PET-derived and measured creatinine and urea clearances were more significant at the 120-minute PET time point compared with the other PET time points. Best correlations were obtained at the fifth and seventh TPD exchanges. D/P ratios for creatinine and urea of the fifth and seventh TPD exchanges correlated significantly with the D/P ratios calculated from total TPD dialysate. A significant correlation was also found between peritoneal creatinine and urea clearances on total dialysate volume (measured clearances) and those derived from the dialysate collection of the fifth and seventh TPD exchanges (estimated clearances)--that based on the seventh exchange being slightly more significant. Moreover, the estimated clearances derived from the seventh exchange were within 10% of the measured value in 90.9% of patients both for creatinine and urea. CONCLUSION: The significant correlation between measured and estimated peritoneal creatinine and urea clearances and the low percentage of underestimates of measured clearances obtained using the seventh TPD exchange-derived indices confirm the accuracy of the D/P ratios for creatinine and urea derived from any exchange after the fifth (preferably the seventh) of a standardized TPD run in estimating peritoneal creatinine and urea clearances. This method could represent a simple and accurate means for prescribing TPD and routinely assessing TPD delivery.

A new test for tidal peritoneal dialysis prescription.

Prediction of suitability of patients for tidal peritoneal dialysis (TPD) treatment based on the peritoneal equilibration test (PET) may be hypothetically subject to errors, due to the difference between the long equilibration times of the PET and the short dwell times currently utilized during TPD. Eleven patients, mean age 12.4 +/- 3.3 years, mean body weight 34.2 +/- 15kg, had both a standardized TPD run (initial fill volume 40 mL/kg, tidal volume 50%, dwell time 10 min, treatment time 8 h) and a PET performed. D/P ratios for creatinine and urea were calculated at the 5th and 7th TPD exchanges (approximating equilibration time of the TPD run), at the time points of the PET and on the total TPD dialysate volume. D/P ratios for creatinine and urea of the 5th and, even more, the 7th TPD exchange, and D/P ratios obtained from total TPD dialysate were significantly correlated overall (r = 0.96, p < 0.0001 for 5th D/P creatinine and urea; r = 0.98, p < 0.0001 for 7th D/P creatinine and urea). Correlation coefficients between PET-derived and total TPD dialysate-derived D/P ratios were generally poor or only modest. Thus, it is possible to predict TPD clearance, and consequently the suitability of patients for TPD, knowing the D/P ratios for creatinine and urea at the 7th TPD exchange of a standardized TPD run. Our data could represent a new reliable test for TPD prescription.

Evaluation of the peritoneal equilibration test in children on chronic peritoneal dialysis.

The peritoneal equilibration test (PET) is routinely performed in adults treated with chronic peritoneal dialysis to assess the peritoneal transport rate and to optimize treatment prescription. Only a few and not well-standardized studies on the PET have been reported in children. Twenty-six PET's were performed in 16 children, mean age 10.9 +/- 4.9 years, mean body weight (BW) 26.8 +/- 11.9 kg, treated with nightly intermittent peritoneal dialysis (NIPD). The PET was performed according to Twardowski. Forty mL/kg BW of 2.27% glucose solution were infused at a rate of 10 mL/kg BW every 2 minutes. In the simplified test, dialysate samples were taken at dwell times 0, 2 and 4 hours for glucose and creatinine. A blood sample was taken after a 2-hour dwell time for the same parameters. The standard PET (8 patients) consisted of dialysate samples at 0, 15, 30, 60, 120, and 240 minutes and blood samples at 0 and 240 minutes. Mean D/P ratio for corrected creatinine and D/D0 ratio for glucose at 2 hours were 51.6 +/- 11.6 and 50.4 +/- 9, respectively; at 4 hours 69.6 +/- 12 and 34.4 +/- 9.8, respectively. There was good correlation between D/P creatinine and D/D0 glucose at 4 hours (p < 0.0001). Patients were classified as high (3 cases), high-average (5), low-average (6), and low (2) transporters. A statistically significant difference was found between the curves obtained by the simplified PET and those of the standard PET in the first hour (r = 0.66; p < 0.05). In conclusion, the PET, modified for use in children, gave reliable and reproducible results.(ABSTRACT TRUNCATED AT 250 WORDS)

Different cascade filtration operating modalities in clinical use.

Cascade filtration (CF) can be performed in either the single-pass or dead-end configuration. The distinction, as predicted by experimental models, is that solute removal is lower but constant in the former, and higher but variable with the quantity of filtrate in the latter. Moreover, unpredictable plugging reduces permeability during operation. It is therefore unclear which configuration is preferable in clinical use. In four cryo- and three macroglobulinemic patients, the data of 10 dead-end CF (QP) and 11 modified single-pass CF with high flow rate recycling plasma (QD) were compared. Both groups had similar starting values. Centrifugal primary plasma separation was performed. No exogenous reinfusions were used. Either 0.8 and 1.2 sq.m. surface secondary filters were employed. The ratio of plasma processed to patients' plasma volume was 1.1 +/- 0.3 in QP, and 0.94 +/- 0.09 in QD. The mean percentage removals of albumin, IgG and IgM respectively were 25.8 +/- 9, 32 +/- 17 and 47.5 +/- 26% in QP, 30.5 +/- 12, 40.5 +/- 19 and 48 +/- 17.5% in QD: albumin vs IgM p less than 0.025 in QP and p less than 0.02 in QD. A/G ratio increased from 1.6 +/- 0.5 to 2.06 +/- 0.6 in QP, and from 1.5 +/- 0.3 to 1.7 +/- 0.3 in QD. Plugging occurred in both groups, requiring 2.3 +/- 1.8 washouts/run in QP vs 1.5 +/- 1.2 in QD. IgM removal was comparable. Removal of albumin and IgG was slightly higher in QD. Similar performances can be obtained with either technique in clinical use, provided an adequate fractionation surface is available.

Selective and semiselective low-density lipoprotein apheresis in familial hypercholesterolemia.

Seven patients with familial hypercholesterolemia were treated fortnightly for 3 months by selective low-density lipoprotein apheresis with dextran-sulfate cellulose column (DSC). Subsequently, 4 of them were treated with semiselective double filtration. No cholesterol-lowering drugs were given. Plasma processed ranged from 39 to 58 ml/kg body weight/procedure. Fractional removals from plasma filtrate at the secondary treatment (adsorption or fractionation) for total cholesterol, high-density lipoprotein cholesterol, and albumin, respectively, were 0.84, 0.06, and 0.03 with DSC and 0.74, 0.47 and 0.35 with double filtration. Postapheresis reductions of total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were 57, 15, and 59% with DSC and 47,35, and 48% with double filtration. Both methods are suitable for clinical use, but with a 15-day treatment schedule, lowering circulating lipid fraction levels are maintained with DSC.

Performance evaluation of cascade filtration with high flow rate recirculating plasma on the secondary filter.

Cascade filtration (CF) has been performed in 67 on-line procedures in 9 normolipidemic patients with paraproteinemic disorders. A modified dead-end technique has been employed, with high flow rate recirculating plasma on the plasma fractionation filter (QD recycled CF), and an albumin-rich, globulin-poor filtrate was reinfused into the patient. Postprocedure recoveries were 81 +/- 15% for albumin, 55 +/- 23% for IgM and 48% for cryocrit, with an increase in A/G ratio from 1.8 to 2.1. An improvement was observed also in antiatherogenic/atherogenic lipoproteins ratio, suggesting a possible use of this technique in the treatment of familial hypercholesterolemia. Plasma primary separation was obtained by centrifugation or by filtration, and no significant differences were observed on subsequent protein fractionation process. An albumin priming of the plasmafractionation circuit accounted for an additional 13% saving in postprocedure level. Different surface area secondary filters have been employed: with larger surfaces, larger volumes were processed without any increase in the waste volume and with reduced need for washouts, but with an additional loss of small molecules possibly due to entrapping onto the membrane.

Efficacy of a combined treatment with plasma exchange and cytostatics in macroglobulinemia.

Monthly plasma exchange (PE) sessions have been carried out in 3 patients with advanced Waldenström macroglobulinemia, in order to reduce electrophoretic M band under 2g/100 ml. When PE was combined to low doses of cytostatics (n = 18), 3 procedures per session were required to obtain a mean 57.4 +/- 12.3% IgM reduction, from 4.2 +/- 1.2 to 1.7 +/- 0.5 g/100 ml. A mean 61.5 +/- 13.1% IgM reduction, from 5.5 +/- 1.3 to 2.1 +/- 1 g/100 ml, was obtained in 64 procedures carried out as the only therapy in 12 sessions, with 5.3 procedures requirement per monthly session. IgM percent reduction 24 hours after PE was greater with combined treatment (45 +/- 9.7 vs. 28.9 +/- 15.4%; p = 0.001). The advantage of a combined treatment is therefore either a lowered PE requirement or a tapered maintenance cytostatic dosage.

Renal abnormalities reverted by plasma exchange in thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is usually accompanied by renal disfunction presumable due to diffuse thrombotic occlusions in the microcirculation. Two patients with TTP and slight renal failure with proteinuria and microscopic hematuria, were treated by repeated plasma exchanges with fresh frozen plasma, associated with prednisone and cyclophosphamide in one case, and prednisone alone in the other one. Platelet count, hematocrit and lactic dehydrogenase reverted to normal values within the fourth exchange; circulating immune complexes were never detected. Plasma factor stimulating prostacyclin activity lacked in only one patient and returned to normal levels after plasma exchange without being affected during a hematologic relapse. Renal function and urinary abnormalities reverted to normal by the end of plasma exchange and nine and six months renal and hematologic follow-up is still negative. Renal abnormalities in TTP seem to take advantage of early treatment by plasma exchange, which further to replacement of missing plasma factors, can account for the removal of toxic substances to be further investigated on.

Plasma exchange in acute renal failure by cortinarius speciosissimus.

Mushroom poisoning by Cortinarius speciosissimus (C. spec.) leading to irreversible renal failure has been described; in a recent report, an expected bad prognosis has probably been overcome as a result of the very early use of hemoperfusion. In Sep. '81, a healthy couple of wife and husband, both aged 38, had gastrointestinal symptoms 2 days after ingestion of C. spec. On day 8 an acute renal failure developed and the same day, before dialysis, plasma exchange (PE) was undertaken. Renal biopsies disclosed a common pattern of tubular necrosis, scattered infiltrates and interstitial edema. Diuresis and partial recovery started in the man on day 10, while failure persisted over six months in the woman. Further to individual sensitivity to C. spec. toxins, renal damage, once established, may be irreversible, irrespectively of early treatment. Limited usefulness of PE in C. spec. poisoning is probably related to the long latency between ingestion and occurrence of the first renal symptoms.