REFINE: a randomized trial comparing cyclosporine A and tacrolimus on fibrosis after liver transplantation for hepatitis C.

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log(10) copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36-0.99) and month 12 (OR 0.33; 95% CI 0.16-0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.

Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis.

Mycophenolic acid, in combination with glucocorticoids, has been shown in a series of trials to be safe and effective for treatment of lupus nephritis. Regimens that permit glucocorticoid dose reduction without loss of efficacy would be advantageous. MyLupus was a 24-week, multicentre, open-label, study in patients with active proliferative lupus nephritis treated with enteric-coated mycophenolate sodium (EC-MPS), randomized to standard-dose (n = 42) or reduced-dose (n = 39) glucocorticoids. Complete response at week 24, the primary endpoint, was achieved in 19.8% (16/81) of patients (19.0% standard-dose, 20.5% reduced-dose; lower limit of 97.5% CI for the difference -15.9%, p = 0.098, i.e. non-inferiority was not shown). Partial response occurred in 42.0% of patients (34/81). From baseline to week 24, the mean global British Isles Lupus Assessment Group (BILAG) score decreased from 14.0 ± 5.4 to 5.0 ± 3.8 (p < 0.001). The incidence of adverse events was 80.2% (65/81), most frequently gastrointestinal complications (31/81, 38.3%). Infections were reported in 57.1% and 35.9% of standard- and reduced-dose glucocorticoid patients, respectively (p = 0.056), with herpes zoster in 16.7% and 0% (p = 0.012). Three patients discontinued study medication due to adverse events. This exploratory study suggests that EC-MPS may facilitate glucocorticoid reduction without loss of efficacy in patients with active lupus nephritis, but results require confirmation in a controlled, longer-term study versus the current standard of care.

Factors influencing renal function after liver transplantation. Results from the MOST, an international observational study.

INTRODUCTION: Renal failure, both acute and chronic, is a common complication after liver transplantation and can seriously jeopardise long-term outcome. Given organ shortage it should be essential to determine which patients will experience progressive and severe renal dysfunction after liver transplantation (LT). AIM: To correlate pre-transplant renal function and risk factors for renal failure after liver transplantation with occurrence of renal failure at 1 and 5 years after LT, with particular attention to hepatitis C virus (HCV) infection. METHODS: Data from patients enrolled in the liver section of Neoral MOST (Multinational Observational Study in Transplantation) study were used for the analysis. HCV status, pre-transplant serum creatinine level, recipient gender, recipient age, pre-transplant arterial hypertension, pre-transplant diabetes mellitus, pre-transplant antiviral therapy, the time of the transplant (before or after 2000) and immunosuppressive regimen were collected for each patient. Post-transplant occurrence of renal failure at 1 and 5 years was defined as a GFR<60 mL/min/1.73 m(2) (Stage III of the National Kidney Foundation). RESULTS: Data from 1948 patients enrolled in the study were considered. Glomerular filtration rate (GFR) was evaluated in 406 patients at 1 year and in 233 patients at 5 years after LT. The prevalence of HCV infection was 35% in the former and 37% in the latter. The median GFR was 70 mL/min/1.73 m(2) after 1 year and 69 mL/min after 5 years, significantly lower in HCV-positive (HCV+) than in HCV-negative (HCV-) patients both 1 and 5 years after LT (p<0.001). GFR before transplant correlated with GFR at 1 month, 1 and 3 years (p<0.0001 for all correlations). Multivariate analysis confirmed HCV status, pre-LT serum creatinine levels and recipient gender as significant predictors of 1-year GFR (p<0.001 for all three). Further analysis of the effect of recipient gender indicated that the only significant risk factor observed in both male and female patients was HCV positivity. Only 1-year GFR was an independent predictor of 5-year GFR (p<0.001). HCV+ status, cyclosporine (CsA) exposure, antiviral therapy and diabetes mellitus had no significant influence on 5-year GFR. CONCLUSIONS: HCV status and pre-LT serum creatinine levels were independent predictors of renal function a year after LT, together with GFR before transplant. The negative impact of HCV positivity on renal function was not confirmed in the long term, whereas the prognostic influence of an abnormal renal function in the early post-transplant period was more persistent.

Long term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid arthritis: a three year study of radiographic progression, renal function, and arterial hypertension.

OBJECTIVE: To compare the three year safety and efficacy of cyclosporin and parenteral gold in the treatment of early, active, severe rheumatoid arthritis (RA), and to study the reversibility of cyclosporin associated renal dysfunction in patients who discontinued cyclosporin treatment. METHODS: The patients continued to receive cyclosporin or parenteral gold in an 18 month open extension to an 18 month randomised, parallel group study. The main efficacy variable was blinded evaluation of radiographic progression of joint damage. Safety variables included serum creatinine, calculated creatinine clearance, and blood pressure. RESULTS: Radiographic progression during follow up was similar in both groups. About 60% of the patients in the intention to treat groups (n=272) and about half of the patients in the completer groups (n=114) had definite radiographic progression in joint damage (increases >6 in the Larsen-Dale score), and about one in three also had substantial progression (>18 increase in Larsen-Dale score). Both systolic and diastolic blood pressure were significantly increased in the cyclosporin group compared with the gold group, and 12/139 (9%) versus 3/139 (2%) (p=0.03) had notably raised blood pressure. The mean serum creatinine increased by 28% at the treatment end point in the cyclosporin group as compared with 7% in the gold group. The mean calculated creatinine clearance was reduced by 16% and increased by 1% in the cyclosporin and gold groups, respectively, at the end of the study. At the final follow up visit after discontinuation of cyclosporin (at least three months after treatment was stopped) the mean serum creatinine was increased by 15% and creatinine clearance reduced by 16%. Sustained increases in serum creatinine at this post-treatment end point were mostly seen in patients with a raised serum creatinine during treatment of at least 50%. CONCLUSION: Three year changes in radiographic damage during cyclosporin and parenteral gold were similar in patients with early, active RA. Abnormal renal function and raised blood pressure were often seen in the cyclosporin treated patients.

A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients.

BACKGROUND: A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS: Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS: During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS: Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.

Comparison of octreotide acetate LAR and lanreotide SR in patients with acromegaly.

BACKGROUND AND OBJECTIVE: The most effective option for the medical treatment of patients with acromegaly is the use of somatostatin analogues. Long-acting depot formulations for intramuscular injection of two somatostatin analogues have recently become available: octreotide acetate LAR (Sandostatin LAR, Novartis Pharma AG) and lanreotide SR (Somatuline, Ipsen Biotech). We wished to compare efficacy of octreotide LAR and lanreotide SR in acromegalic patients. PATIENTS AND METHODS: A group of 125 patients with acromegaly (67 females; mean age, 47 years; 59 patients had previous pituitary irradiation) from 26 medical centres in France, Spain and Germany were studied. Before the study, all patients had been treated with intramuscular injections of lanreotide SR (mean duration, 26 months) at a dose of 30 mg which was injected every 10 days in 64 and every 14 days in 61 patients, respectively. All patients were switched from lanreotide SR to intramuscular injections of 20 mg of octreotide LAR once monthly for three months. In order to obtain efficacy and safety data of lanreotide SR under study conditions, it was decided to randomly assign at day 1, in a 3 : 1 ratio, the time point of the treatment switch; 27 of the patients were randomly assigned to continue the lanreotide SR treatment for the first 3 months of the study (group A); they were on octreotide LAR 20 mg from month 4-6. The other 98 patients were assigned to be switched to treatment with octreotide LAR 20 mg at day 1 (group B). In group B patients, octreotide LAR treatment was continued until month 6, with an adjustment of the dose based on GH levels obtained at month 3. RESULTS: The mean GH concentration decreased from 9.6 +/- 1.3 mU/l at the last evaluation on lanreotide SR to 6.8 +/- 1.0 mU/l after three injections of octreotide LAR (P < 0.001). The percentages of patients with mean GH values < or = 6.5 mU/l (2.5 microg/l) and < or = 2.6 mU/l (1.0 microg/l) at the last evaluation on lanreotide SR were 54% and 14%, and these values increased after 3 months treatment with octreotide LAR to 68% and 35% (P < 0.001), respectively. IGF-I levels were normal in 48% at the last evaluation on lanreotide SR and in 65% after 3 months on octreotide LAR (P < 0.001). Patients with pre-study pituitary irradiation had lower mean GH and IGF-I concentrations. But the effects of the treatment change did not differ between the irradiated and the nonirradiated patients. In general both drugs were well tolerated. CONCLUSION: Octreotide LAR 20 mg administered once monthly was more effective than lanreotide SR 30 mg administered 2 or 3 times monthly in reducing GH and IGF-I in patients with acromegaly.

Progression of joint damage in early active severe rheumatoid arthritis during 18 months of treatment: comparison of low-dose cyclosporin and parenteral gold.

OBJECTIVE: This study compared the progression of joint damage in patients with early active severe rheumatoid arthritis (RA) treated with cyclosporin or parenteral gold. METHODS: In this open, randomized, multicentre study with a blinded radiological endpoint, 375 patients who had suffered from active severe RA for <3 yr were randomized to be treated for 18 months with low-dose cyclosporin or parenteral gold. The groups were stratified with regard to corticosteroid use. Primary efficacy variables were numbers of erosions, erosion score and the Larsen-Dale joint damage score. RESULTS: Joint damage progressed at similar rates in both treatment arms. In both groups, patients receiving corticosteroids had less X-ray progression. Rheumatoid factor positivity, high swollen joint count, high erythrocyte sedimentation rate and pre-existing X-ray abnormalities predicted progression of joint damage. Although numbers of serious adverse events were similar, more gold patients (n = 65) than cyclosporin patients (n = 45) withdrew from study medication because of adverse events. CONCLUSION: Cyclosporin was comparable to parenteral gold in retarding progression of joint damage and was better tolerated in terms of adherence to therapy. The open label design should be kept in mind when assessing this difference.

Analgesic effect of the somatostatin analogue octreotide in two acromegalic patients: a double-blind study with long-term follow-up.

Two acromegalic patients with severe headache were treated with the somatostatin analogue, octreotide (Sandostatin). A double-blind study of octreotide versus placebo in which pain intensity was measured using a visual analogue scale (VAS) was performed initially with these patients. A rapid (within 4-15 min) pain relief occurred lasting 2-8.5 h after injection of 100 micrograms of octreotide, an effect that was not reversed by intravenous (i.v.) naloxone. These 2 acromegalic patients then received treatment for 71 and 82 months, respectively, with doses starting at 500 micrograms/day and 1500 micrograms/day, respectively, without evidence of either tolerance or dependence, although the effect of octreotide on headache appears to be selective. No unwanted sedative effect has been observed. A screening procedure with injection of 50 micrograms of subcutaneous (s.c.) octreotide was performed in 11 other patients with chronic severe pain associated with various conditions. Only 3 patients (2 with diabetic polyneuropathy and 1 with bone pain associated with myelodysplastic syndrome) reported more than 50% pain relief. In the insulin-dependent diabetic patients the double-blind check was not performed due to the risk of octreotide-induced hypoglycemia. In the patient with bone pain the same double-blind check as in the acromegalic patients could not confirm the analgesic effect. It may thus be concluded that octreotide appears to be useful for the treatment of both chronic and acute severe painful conditions in acromegalic patients. However, since its analgesic effect in our patients was confined to headaches only, further controlled studies must be carried out in order to determine appropriate target groups.

Effects of long-term ergoloid mesylates ('Hydergine') administration in healthy pensioners: 5-year results.

Five-year results are reported of a controlled long-term comparative study to assess the effects of ergoloid mesylates (1.5 mg 3-times daily) and placebo on medical, psychological and electrophysiological variables. Initially, 148 healthy elderly volunteers of both sexes were included. Eighty-nine subjects (48 on ergoloid mesylates and 41 on placebo) are still in the double-blind study; 39 subjects have left the trial for various reasons (6 deaths, 25 drop-outs due to disease, and 8 withdrawals) and 20 subjects are participating under 'open' conditions. Formal statistical comparison of the two groups in terms of 10 medical and psychometric outcome variables did not produce significant differences. However, a number of relevant findings and trends with regard to the effects of ergoloid mesylates were established: the drug was well tolerated objectively and subjectively; subjective complaints such as frequent dizziness, cardiac symptoms and leg cramps were improved; there was less increase than on placebo in the number of subjects with pathological ECG findings; there was less increase than on placebo in the number of subjects taking digitalis; fewer subjects than in the placebo group had an increase in the number of major diagnoses; the decrease in some lipid fractions was more pronounced than on placebo; and performance in some psychometric tests (WAIS Vocabulary, WAIS Performance) was better in the ergoloid mesylates group. None of these findings, by itself, would be evidence of a dramatic effect of ergoloid mesylates on the participants in the double-blind trial. Taken together, however, they fall into a pattern, suggesting that ergoloid mesylates was partly effective in maintaining physical and mental health in these healthy elderly individuals. The finding of more disease-related and symptom-related drop-outs in the placebo group (25 vs. 20 in the ergoloid mesylates group) supports this assumption. Furthermore, the fact that a number of subjects who had left the double-blind trial for medical reasons improved on subsequent ergoloid mesylates administration may be seen as a further argument in favour of a prophylactic effect of ergoloid mesylates on pathological concomitants of ageing.

[Pharmacokinetic studies following intravenous, intramuscular and rectal administration of methohexital in children]. / Pharmakokinetische Untersuchungen nach intravenöser, intramuskulärer und rektaler Applikation von Methohexital bei Kindern.

In pediatric patients methohexitone is used increasingly in different application forms for induction of anesthesia. Plasma concentrations of methohexitone were measured after rectal induction with 25 mg/kg, and after intramuscular injection of 5 mg/kg in 10 children each aged 2-7 years and were compared with 4 children after intravenous administration of 2 mg/kg. The pharmacokinetic parameters of the i.v. administered methohexitone were calculated and compared with the known pharmacokinetics in adults, showing that the open two-compartment-model is also applicable to children with a substantial shorter beta-half-life and a higher clearance. After rectal and i.m. induction with methohexitone the individual plasma concentrations scatter in a relatively wide range. The mean value curves of both application forms are similar with a maximum plasma concentration of 2.76 micrograms/ml between minutes 7-15 (rectal) respectively 2.6 micrograms/ml between minutes 15-30 (i.m.); 2 h later they are 0.57 micrograms/ml (rectal) and 1.03 micrograms/ml (i.m.). In contrast to the 100% available bioactivity of methohexitone after i.m. administration it amounts to only about 17% after rectal induction. As a result one can consider children to be able to eliminate methohexitone sufficiently in the observed plasma concentration range.

[Carbohydrate infusion in internal diseases. A comparative study in metabolically health, liver diseased and diabetic patients. VII. Infusions of a glucose-fructose-xylitol mixture (relationship 1:2:1) over 48 hours]. / Kohlenhdratinfusion bei internistischen Erkrankungen. Eine vergleichende Studie bei stoffwechselgesunden, leberkranken und diabetischen Patienten. VII. Infusion eines Glukose-Fruktose-Xylit-Gemisches (Verhältnis 1:2:1) über 48 Stunden.

3 groups (6 control persons, 6 patients with liver cirrhosis, 6 patients with diabetes mellitus) were infused with 20% (w/v) carbohydrate mixture (glucose/fructose/xylitol, 1:2:1) for 48 hours. The metabolical status was controlled in defined intervals by means of 39 different laboratory parameters. The infusion rate was supposed to be 0.25 g carbohydrates/kg B. W. and hour. There were no significant changes in blood glucose levels in any of the 3 groups. However we could observe a slight but constant increase in lactate and triglyceride concentrations. Free fatty acids and keton bodies were suppressed on a low level. Only the diabetics showed a significant renal carbohydrate loss with up to 15% of the amount administered. No clinically relevant side effects were observed.

[Carbohydrate infusion in internal diseases. A comparative study in metabolically healthy, liver diseased and diabetic patients. VI. Infusions of a glucose/xylitol mixture (1:1 ratio) over a 48-hour period]. / Kohlenhydratinfusion bei internistischen Erkrankungen. Eine vergleichende Studie bei stoffwechselgesunden, leberkranken und diabetischen Patienten. VI. Infusion eines Glukose/Xylit-Gemisches (Verhältnis 1:1) über 48 Stunden.

By central venous catheterization, 6 control persons, 7 patients with liver cirrhosis and 6 patients with diabetes mellitus were infused for 48 h with a 20% (w/v) mixture of glucose/xylitol (1:1). The infusion 48 h with a 20% (w/v) mixture of glucose/xylitol (1:1). The infusion rate of 0.125 g monosaccharide/kg/h could be maintained with minor deviations. There were no significant changes in blood glucose levels using this infusion regimen. Lactate levels, however, did increase constantly during the whole infusion period. In the liver group as well as in the diabetic group we could measure values between 1.5 and 3.9 mmol/l. Triglycerides increased solely in the diabetic group. Uric acid concentrations were elevated in all 3 groups. Clinically significant side effects were not observed.

[Carbohydrate infusions in internal diseases. A comparative study in metabolically normal subjects, patients with liver diseases and diabetics. V. Infusion of a glucose-sorbitol mixture (ratio 1:1) for 48 hours]. / Kohlenhydratinfusion bei internistischen Erkrankungen. Eine vergleichende Studie bei stoffwechselgesunden, leberkranken und diabetischen Patienten. V. Infusion eines Glukose-Sorbit-Gemisches (Verhältnis 1:1) über 48 Stunden.

Three groups (6 patients with liver cirrhosis, 6 patients with diabetes mellitus, 6 controls) have been infused for 48 h with a 20% (w/v) glucose/sorbitol-solution (1:1). The only group where the infusion rate of 0,25 g carbohydrates/kg/h could not be reached was the control group with 0,232 g carbohydrates/kg/h. We could not see any significant changes in blood glucose levels during the total infusion period. Sorbitol levels dropped very slowly after the end of the infusion, a time when sorbitol was still excreted in the urine. The concentration of triglycerides was steadily increasing. Besides there were no further changes compared to equicaloric glucose or glucose/fructose infusions.

Correlations of the receptor content and ultrastructure of breast cancer cells.

Receptor assay results were compared with the ultrastructure of 127 breast cancers (112 primary tumors, six recurrent lesions, nine metastases). Tumors were considered to be receptor positive if the receptor levels were greater than or equal to 15 fmol/mg of soluble tissue protein. Most breast cancer had heterogenous cells with different grades of ultrastructural differentiation. a prevalence of well-differentiated cancer cells and an abundance of intracytoplasmic vacuoles had a significant correlation with a positive estrogen receptor status. The correlation was better than between malignancy grades and receptor content. The type of breast cancer and the menopausal status bore no relation to receptor content. Progesterone receptors were found in well-differentiated tumors of low malignancy.

Prognostic significance of the steroid receptor content in primary breast cancer.

Recurrence and survival rates were studied in 222 patients with primary breast cancer with particular reference to relations with the estrogen and progesterone receptor content of the primary tumor, involvement of axillary lymph nodes and menopausal status. The median observation time for these 222 women was 46 months, the longest being 88 months and the shortest for recurrence-free survivors, being 42 months. Within the first 4 years after primary surgery, recurrences occurred more rarely and later in patients with receptor-positive cancers. After 70 and 50 months, respectively, there was no longer any difference between estrogen receptor- and progesterone receptor-positive and receptor-negative cases. The overall survival curve plotted in accordance with Kaplan and Meier [5] was more favourable for patients with estrogen receptor-positive carcinoma than for those with estrogen receptor-negative tumors, even after 6.5 years.