Epoetin theta: efficacy and safety of IV administration in anaemic haemodialysis patients in the maintenance phase in comparison to epoetin beta.

OBJECTIVE: To compare the efficacy and safety of epoetin theta and epoetin beta in anaemic patients with chronic kidney disease, undergoing haemodialysis and previously on stable maintenance therapy with epoetin beta. METHODS: In this multicentre, randomised, controlled, double-blind study 270 haemodialysis patients were treated intravenously (i.v.) for 24 weeks with either epoetin theta (n = 180) or epoetin beta (n = 90). The primary efficacy endpoint was the change in haemoglobin (Hb) from baseline to end of treatment (efficacy evaluation period, EEP, weeks 15-26). Hb levels, weekly doses of epoetin theta or epoetin beta required to maintain Hb levels, dose changes, safety, tolerability and immunogenicity were evaluated. CLINICAL TRIAL REGISTRATION: EudraCT No. 2005-000143-28. RESULTS: Mean Hb values were similar in both treatment groups at baseline and during the 24-weeks treatment period. The estimated treatment difference between epoetin theta and epoetin beta from baseline to EEP was -0.01 g/dL (95% confidence interval: -0.24, 0.21), p = 0.9021, indicating that the difference between both groups was not statistically significant. The weekly doses of epoetin theta or epoetin beta required to maintain Hb levels were nearly the same. The changes from baseline to EEP in patients who switched to treatment with epoetin theta (95.5-99.7 IU/kg(BW)) were smaller than in patients staying on their epoetin beta therapy (89.0-98.0 IU/kg(BW)). The profile and the frequency of adverse drug reactions (ADRs) were similar in both treatment groups (21.7% epoetin theta; 22.2% epoetin beta). The most common ADRs were hypertension, headache and arteriovenous fistula thrombosis. None of the patients developed anti-erythropoietin antibodies. CONCLUSIONS: Epoetin theta (i.v.) has a similar efficacy compared to epoetin beta (i.v.) in haemodialysis patients based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was similar in both groups. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes.

Acute Treatment of Facet Syndrome by CT-Guided Injection of Dexamethasone-21-Palmitate Alone and in Combination with Mepivacaine.

OBJECTIVE: To compare the efficacy and tolerability of dexamethasone-21-palmitate and mepivacaine alone and in combination in the acute treatment of facet syndrome. PATIENTS AND METHODS: A total of 157 patients requiring acute therapy for lumbar facet syndrome were treated with computed tomography (CT)-guided intra-articular infiltration of either an anti-inflammatory corticosteroid, a local anaesthetic or a combination of the two. Patients assigned to the first treatment group (n = 60) received the corticosteroid dexamethasone-21-palmitate (Lipotalon((R))); patients in the second group (n = 36) received the local anaesthetic mepivacaine (Meaverin((R))); patients in the third group (n = 61) received a combination of the two drugs. The study duration was from November 2002 until June 2003. RESULTS: In all three groups, values for compression pain, stress pain and rest pain improved significantly from baseline within 1 hour of injection: in the dexamethasone monotherapy group there was a 13% reduction in compression pain, 20% reduction in stress, and 22% reduction in rest pain; in the groups that received mepivacaine only or a combination of the two drugs there was a 63% and 60%, respectively, reduction of compression pain, 81% and 83%, respectively, reduction of stress pain, and 84% and 77%, respectively, reduction of rest pain. After 72 hours, improvements in these variables were significantly greater in patients treated with dexamethasone-21-palmitate (either as monotherapy or in combination therapy) than in patients treated with mepivacaine alone. In both groups treated with dexamethasone palmitate there was a 57% and 64%, respectively, reduction of compression pain, 70% and 66%, respectively, reduction of stress pain, and 75% and 64%, respectively, reduction of rest pain. In the mepivacaine monotherapy group there was a 17% reduction in compression pain, 26% reduction in stress pain and 13% reduction in rest pain. Both physicians and patients also rated the dexamethasone-21-palmitate-containing regimens as more effective than mepivacaine alone at 72 hours. Over the entire observation period, combination therapy was, on average, superior to both monotherapy regimens. The proportion of patients using concomitant NSAID medication after 3 days was reduced by 50% in the mepivacaine group and by 76% and 100%, respectively, in the dexamethasone-21-palmitate and combination therapy groups. CT-guided infiltration treatment was well tolerated and was associated with virtually no side effects in this study. CONCLUSION: CT-guided infiltration of dexamethasone palmitate, particularly in combination with mepivacaine, represents a safe and effective method for the acute therapy of lumbar facet syndrome. The combination is superior to the local anaesthetic alone with regard to pain reduction up to 3 days after injection.

M2/M2 side-to-side rescue anastomosis for accidental M2 trunk occlusion during middle cerebral artery aneurysm clipping: technical note.

OBJECTIVE: A technically feasible and rapid technique for revascularizing the main branches of the middle cerebral artery (MCA) is described. This technique is applied mainly when clipping of an MCA aneurysm is complicated and occlusion of the origin of an MCA main branch results. METHODS: M2/M2 side-to-side anastomosis was applied in two patients in whom unplanned M2 occlusion occurred during the course of complicated MCA aneurysm clipping. The first patient underwent an emergency procedure after temporoparietal intracerebral hemorrhage. Unilateral mydriasis precluded preoperative angiographic workup, and a complex large MCA aneurysm was found as the source of hemorrhage. Shaping of the aneurysm neck by bipolar coagulation and clipping resulted in accidental occlusion of the superior trunk, and patency could not be regained despite multiple clip corrections. The second patient had an unruptured multilobulated aneurysm 8 mm in maximum diameter. Continuity of the inferior trunk was lost during clipping because of a tear at the origin. In both instances, side-to-side anastomosis was placed approximately 15 mm from the bifurcation, where the MCA main trunks ran side by side for a length of approximately 5 mm. RESULTS: After intracerebral hemorrhage, the first patient recovered to a level of moderate disability within 2 months. Substantial hemiparesis and expressive dysphasia remained as sequelae of the intracerebral hemorrhage. Digital subtraction angiography 2 months after the emergency procedure confirmed patency of the side-to-side anastomosis. The second patient was neurologically intact after recovery from anesthesia. Before discharge from the hospital on postoperative Day 8, digital subtraction angiography confirmed patency of the anastomosis. CONCLUSION: The MCA main branches usually run in close proximity for a short segment at the bottleneck entrance to the insular cistern. M2/M2 side-to-side anastomosis at this site is a rapid and feasible mode of revascularization of an M2 trunk accidentally occluded during complicated MCA aneurysm clipping.

Acute and chronic anti-inflammatory properties of [2,2-dimethyl-6-(4- chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid.

The carrageenan-induced paw oedema in the rat was chosen as the experimental model for acute antiphlogistic activity. ED50 values of 3 mg/kg p.o. for indometacin and of 17 mg/kg p.o. for [2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2, 3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000) at calculated plasma levels (micrograms/ml) of approximately 5.0 and 20.0 were recorded for indometacin and ML 3000, respectively. The activity ratio of indometacin: ML 3000 is therefore about 1:6 with regard to the oral dose and about 1:4 with regard to the calculated plasma level. Indometacin is more potent than ML 3000 on the one hand, but on the other hand ML 3000 is better tolerated by the stomach in this experimental study: the ulcerogenic dose UD50 (indometacin) is 7 mg/kg p.o., whereas ML 3000 is tolerated well up to the highest tested dose of 100 mg/kg p.o. The adjuvant arthritis in the rat served as the model for chronic antiphlogistic activity. ML 3000 at doses of 20 mg/kg/d p.o. and higher, and indometacin at a dosage of 2 mg/kg/d p.o. produced a similar rate of reduction of the adjuvant-induced secondary lesions and paw swelling of the injected and uninjected paws, following prophylactic as well as therapeutic treatment with the compounds.

Gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl-7-phenyl- 2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid in the rat.

The gastrointestinal tolerance of [2,2-dimethyl-6-(4-chlorophenyl)-7- phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid (ML 3000, CAS 156897-06-2) has been tested in comparison with indometacin, after both single and multiple administrations for 5 and 11 days in an in vivo rat assay. A single oral administration of ML 3000 at doses of 10, 30 and 100 mg/kg produced no gastrointestinal damage. Repeated oral administration of ML 3000 at daily doses of 10, 30 and 100 mg/kg produced slight gastrointestinal damage, but the effect was minimal and was not found to be statistically significant. Indometacin produced highly statistically significant gastric and duodenal damage following one single administration of 10 mg/kg. Repeated oral administration, at 3 mg/kg each day, produced moderate and statistically significant gastric and slight duodenal damage on Day 5 of dosing. However, by Day 11 pronounced duodenal damage was observed which was shown to be statistically highly significant. These results indicate that ML 3000 is clearly better tolerated by the gastrointestinal tract than indometacin after single and multiple administration up to 11 days in rats.

Safety and efficacy of lifibrol upon four-week administration to patients with primary hypercholesterolaemia.

The efficacy and safety of lifibrol, a novel cholesterol-lowering drug, was investigated in a double-blind clinical study in 168 patients with primary hypercholesterolaemia. Placebo and four lifibrol dose groups (150, 300, 450 and 600 mg/day) were tested over a period of 4 weeks. The mean LDL-cholesterol changes were 5.7%, -11.1%, -27.7%, -34.5% and -35.0%, respectively, after 4 weeks of treatment. No major changes in HDL-cholesterol were seen after this period. With the present study design, a decrease in triglycerides (-28%) was significant in the highest dosage group only. Additionally, it was shown that further independent risk factors for coronary heart disease were favourably influenced. Fibrinogen decreased in all dosage groups with a maximal mean value of 18% and a tendency toward reduction in lipoprotein (a) was observed in patients with high baseline levels (> 30 mg.dl-1). Lifibrol was generally well tolerated in all dosage groups and no serious adverse events were reported. Laboratory parameters did not show any clinically relevant alterations.