Physicochemical, biological, functional and toxicological characterization of the European follow-on glatiramer acetate product as compared with Copaxone.

For more than 20 years, Copaxone (glatiramer acetate, Teva), a non-biological complex drug, has been a safe and effective treatment option for multiple sclerosis. In 2016, a follow-on glatiramer acetate product (FOGA, Synthon) was approved in the EU. Traditional bulk-based methods and high-resolution assays were employed to evaluate the physicochemical, functional, and bio-recognition attributes, as well as the in vivo toxicity profile of the active substances in Copaxone and Synthon EU FOGA lots. These tests included quality control tests applied routinely in release of Copaxone lots, as well as additional characterization assays, gene expression studies and a rat toxicity study. Even though the Synthon FOGA was designed to copy and compete with Copaxone, the active substances were found to be similar in only 7 of the tested 14 (50%) methods (similar is defined as within approved specifications or within the inherent microheterogeneity range of tested Copaxone batches, or not showing statistically significant differences). With additional methods applied, consistent compositional differences in attributes of surface charge distribution, molecular size, and spatial arrangement were observed. These marked differences were concordantly observed with higher biological activity of some of the Synthon EU FOGA lots compared with Copaxone lots, including potency and cytotoxicity activities as well as gene expression of pathways that regulate apoptosis, IL-2, and inflammation signaling. These observations raise concerns for immunogenicity differences, particularly in (repeated) substitution settings. Another orthogonal finding demonstrated increased frequency of injection-site local toxicity observations for the Synthon EU FOGA in an in vivo daily dosing rat study, thus warranting further qualification of the link between compositional and functional differences in immunogenicity, and potential impact on long-term efficacy and safety.

New retrievable coil anchors: preliminary in vivo experiences in swine.

PURPOSE: To design and test retrievable coil anchors to improve the safety and efficacy of coil embolization. METHODS: Fifty-two 0.038-inch homemade retrievable stainless steel coils were equipped with one of four different pre-shaped nitinol anchors and tested in 38 pigs. All coils with the anchor were completely retrieved and redeployed 3-18 times (median 7 times) prior to release. Types 1 and 2 anchored coils were acutely deployed in the external iliac arteries (n = 10 each), and chronically tested (1 week) in the common carotid arteries (n = 6 each). Larger type 1 (n = 4), type 3 (n = 6), and type 4 (n = 4) anchored coils were acutely deployed in the abdominal aorta. The largest type 1 anchors (n = 6) were acutely tested in the inferior vena cava. RESULTS: All anchored coils were successfully retrieved and repositioned several times. All but two coils formed a compact plug and there was no coil migration except with two mechanically defective type 3 anchors. CONCLUSION: The use of retrievable anchors allowed the coils to be retrieved and repositioned, prevented coil migration, and enabled compact coil configuration.

Etiprednol dicloacetate, a new soft glucocorticoid drug candidate. Development of chemistry.

During development of chemistry of the soft drug candidate etiprednol dicloacetate (BNP-166) 1) optimization studies on the three-step chemical synthesis resulted in a process that could be scaled-up to the kg level, 2) the impurity profile was determined, 3) synthetic routes were developed for the preparation of the radiolabeled target compound, and 4) a series of hydroxylated metabolites was prepared.

New embolization coil containing a nitinol wire core: preliminary in vitro and in vivo experiences.

PURPOSE: To improve the stability of the standard stainless steel embolization coil by adding a nitinol wire core. MATERIALS AND METHODS: With use of one coil with a nitinol wire core and one without one, stability and resistance to elongation were measured in vitro. Thirty-one factory-made stainless-steel macrocoils equipped with preshaped nitinol wire cores were acutely deployed into branches of the superior mesenteric artery (SMA) in five pigs (part I of the study). Fifteen homemade retrievable coils with thermal shape memory (TSM) nitinol wire cores were acutely deployed in the abdominal aortae or inferior venae cavae of four pigs (part II). Coils with a superelastic (SE) nitinol wire core (n = 9), a TSM nitinel wire core (n = 5), and without a core (n = 5) were compared in carotid embolization (part III). RESULTS: In vitro, the expansile strength of the reinforced coils was significantly greater and elongation was significantly less than the standard coils (P <.01). In part I, coils were easily deployed via diagnostic catheters. In part II, ability to reposition the coils facilitated optimal coil configuration, which resulted in effective self-anchoring and occlusion. In part III, no coils with a SE core migrated, whereas one of five with a TSM core and three of five without reinforcement migrated immediately. The core significantly increased coil stability and postplacement configuration (P <.01). CONCLUSIONS: Addition of a nitinol wire core increases the intravascular stability of the standard embolization coil by significantly enhancing expansile force and postplacement configuration. The wire core does not adversely affect the handling of the coil. The ability to reposition/retrieve the coil is a desirable feature.

A double coaxial delivery system for deployment of a two-stage stent-graft. An experimental feasibility study.

PURPOSE: To design and test a delivery system for successive, rapid two-stage deployment of an aortic stent graft. MATERIAL AND METHODS: An aortic stent graft was made that consisted of two separate parts. A delivery system composed of two independent coaxial mechanisms was fabricated and used to deploy the stages of the graft in dogs' aortas. RESULTS: Delivery was successful in all four dogs, and required less than 2 min in each animal. CONCLUSION: The double coaxial delivery system enabled quick endovascular assembly of a two-stage aortic stent-graft.

Preliminary results with a new vascular basket occluder in swine.

PURPOSE: To experimentally evaluate a new self-anchoring vascular occlusion device suitable for use in large, high-flow vessels. MATERIALS AND METHODS: A basket-shaped occluding device consisting of a nitinol frame (with or without polyester threads) covered with Dacron was evaluated in the common iliac arteries and abdominal aortae of normal pigs. One occluder was placed in each recipient vessel. Angiography was performed before and after placement of each occluder. RESULTS: Precise placement of the device was achieved in all cases. Mechanically, all but one occluder worked dependably. Angiographically, devices without polyester threads produced only partial occlusion. Devices with threads produced complete occlusion in all but one abdominal aorta, in which partial occlusion occurred because the occluder opened asymmetrically. Complete iliac arterial occlusion occurred within 2-8 minutes of placement and aortic occlusion was achieved within 8-20 minutes. At necropsy, all devices were found to be securely anchored against the vascular wall. CONCLUSION: Preliminary results indicate that this vascular basket occluder containing polyester threads is easy to place precisely, produces rapid embolization, and demonstrates good self-anchoring ability in a high-flow arterial model.

Anchoring coil embolization in a high-flow arterial model: a pilot study.

PURPOSE: To devise and test an occluding coil anchoring system to improve the safety of coil embolization. MATERIALS AND METHODS: The anchoring system was attached to Gianturco embolization coils and investigated in 15 pigs. In the short-term studies, one 0.035-inch anchored coil (15-18 cm in length and 7-10 mm in diameter) was placed in the infrarenal portion of the abdominal aorta in each of 12 pigs with use of an 8-F catheter from the carotid approach. Aortography was performed before and up to 4 hours after coil placement. In the long-term studies, 0.028-inch anchored coils (8 cm in length and 5 mm in diameter) were placed in the left femoral and the right carotid arteries in each of three pigs with use of a 6-F catheter positioned from the right femoral approach. One week later, the animals were evaluated angiographically for coil migration and vascular occlusion. RESULTS: Radiographically, the coils created a compact conglomerate on placement in all but one of the animals. No coil migration was noted during follow-up. Necropsy confirmed compact arrangement of the coils within the vessels and revealed effective anchoring of the device in all cases. CONCLUSIONS: The anchoring coil has proved effective in making coil embolization safer, especially in a high-flow arterial model.

Microbial conversion of mevinolin.

About 3000 microorganisms (bacteria, Actinomyces, Zygomyces, Deuteromyces) were screened for their capacity to convert mevinolin. Absidia coerulea IDR 705 was found to produce two hydroxylated derivatives of mevinolin, 2 and 3. Compound 2 is a new transformation product while compound 3 was described as a chemical modification product of mevinolin. By combination of spectroscopic techniques, the structures of 2 and 3 were identified with beta,delta-dihydroxy-7-(1,2-dihydro-2-hydroxymethyl-6-methyl-naphthal en-1-yl)-heptanoic acid delta-lactone and beta,delta-dihydroxy-7-[1,2,3,5,6,7,8,8a-octahydro-3,5-dihydroxy-2, 6-dimethyl-8-(2-methyl-butyryloxy)-naphthalen-1-yl]-hepta noi c acid delta-lactone, respectively. The inhibitory effects of the two derivatives on the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase were similar to that of mevinolin.

Technical aspects of catheter-related interventions in the liver of the rabbit.

PURPOSE: On the basis of 89 different vascular interventions performed in the livers of 39 rabbits, we attempted to establish the feasibility and technical limitations of these procedures. MATERIAL AND METHODS: Forty-five selective hepatic artery catheterizations were carried out using 0.66-mm and 1.0-mm catheters, including superselective proper hepatic catheterizations (n = 14) using a specially designed 0.66-mm introducer/catheter system. The portal system was investigated with both direct (n = 5) and indirect (arterial) (n = 4) portography. Hepatic, vein catheterizations were performed in 22 cases. RESULTS: With the 0.66-mm system, spasm occurred in one of 11 cases in the proper hepatic artery, and no spasm was observed in the common hepatic and celiac arteries. Both arterial portography and hepatic venography were easily performed and were a precise and repeatable method. CONCLUSION: The 0.66-mm system has proved to be advantageous over the 1.0-mm catheterization in avoiding arterial spasm. Direct portography as well as catheterization of the hepatic vein from a jugular approach are hazardous, leading to serious complications including the death of the animal.

Superselective arterial catheterization in the rabbit.

RATIONALE AND OBJECTIVES: To improve the safety and success of selective and superselective arterial catheterization in the rabbit. METHODS: A 2-F catheter introducer system was devised that consisted of the sheath of an 18-gauge, 5.1-cm sheath needle and a hemostatic valve attached to the hub of the sheath. The system was tested in 14 adult male New Zealand white rabbits with regard to ease of insertion and facilitation of superselective arterial catheterization. RESULTS: The introducer system was easily placed in all rabbits, and no bleeding was seen around the sheath at the puncture site. Preshaped 2-F polyethylene catheters were readily inserted through the assembly and sheath. The valve prevented bleeding from around the catheter, and the side-arm flush tube served as a route for heparinization. The system greatly facilitated the manipulation of 2-F angiographic catheters. CONCLUSION: Use of the introducer system with a 2-F polyethylene angiographic catheter improved the success of selective and superselective arterial catheterization in the rabbit.

[Results of combined multicycle locoregional therapy in the palliative treatment of multiple liver metastases]. / Többciklusú kombinált locoregionalis terápiával elért eredményeink multiplex májmetastasisok palliatív kezelésében.

Twenty eight patients with multiple liver metastases were treated by locoregional intraarterial chemotherapy including 118 (3-7, mean 4.2) cycles. In the majority of patients the treatments were carried out in the form of combined cytostatic infusions into the hepatic artery using 5-FU, doxorubicin, cisplatin and mitomycin-C and were complemented by transcatheter embolisation, chemoembolisation and lipiodolisation. In some patients the lipiodolisation was choosen as the primary treatment. In patients with metastases from breast cancer (n = 11) 3 CR, 6 PR, 2 MR occured, the mean survival was 18.4 months, while the one- and two-year survival was 7/11 and 4/11, respectively. In the colorectal group (n = 10) 0 CR, 6 PR, 4 MR were achieved with a mean survival of 13.6 months; one-year survival was 5/10. In the third group (n = 7) consisting of also patients with the poorest prognosis a mean survival of 11.5 months (referring to 6/7 patients) could be accomplished. A patient with metastases from a retroperitoneal anaplastic carcinoma is still alive and disease-free for 92 months. Authors emphasise the importance and effectiveness of locoregional treatments in improving the quality of life as well as survival of patients with unresectable liver metastases.

[Interventional radiology in pediatrics]. / Az intervenciós radiológia lehetöségei gyermekkorban.

A survey of therapeutic possibilities offered by pediatric interventional radiology is given. Authors emphasize that the percutaneous interventional radiology procedures are performed either as an adjuvant treatment facilitating other (surgical) methods or as definite therapy replacing traditional treatment modalities. It is also stressed that interventional procedures are cost effective and relative less expensive than surgery, and they are not so cumbersome to the patients and can shorten the time for hospitalization significantly. Authors present 5 illustrative cases including locoregional chemotherapy and embolotherapy of liver tumors, transcatheter embolization for a varicocele, an arteriovenous malformation and an aneurysmal bone cyst.

[Treatment methods for malfunctioning endoprostheses]. / Epeúti endoprotézisek rendellenes müködésének kezelési módjairól.

A survey on treatment options for salvation of malfunctions of biliary endoprostheses is given. If the anatomical situation makes it feasible the endoscopic procedure should be preferred which is less cumbersome to the patient. Percutaneous interventions may include procedures from the mechanical unclogging of the lumen to the removal and changing of the occluded endoprosthesis. The authors emphasize the advantages of the endoprostheses over the external-internal drainage even if interventionalists should count on even multiple changing of endoprostheses due to their tendency to occlusion in patients with a tumor ensuring relative long life expectancy.

[Oily contrast medium used for chemoembolization in the palliative treatment of extensive inoperable primary hepatocellular carcinomas]. / Olajos kontrasztanyaggal végzett kemoembolizáció nagy kiterjedésü inoperabilis primer hepatocellularis carcinomák palliatív kezelésében.

Transcatheter arterial oily chemoembolization using cytostatics mixed with lymphographic contrast agent with or without Gelfoam embolization seems currently to be the most suitable treatment for unresectable hepatocellular carcinomas (HCC). 5 patients with inoperable, biopsy proven huge HCC (average size 404 cm2) were treated by multiple cycles (3-7, average 4.6 cycles) of a triple drug combination including doxorubicin, cisplatin and mitomycin-C together with Lipiodol. In 13/23 cycles the lipiodolization was complemented by Gelfoam embolization increasing the efficacy of treatment. The hypervascular HCC-s showed marked reduction in size (degree of regression was 33-66%, average 55%). The median follow-up was 1918 (13-36 months). Three patients are still alive with follow-up ranging from 15-36 months (average 23 months) despite the progression of the disease. One patient died of tumorous cachexia 13 months after initial treatment, while another one, who developed partial remission, lost his life in a road accident 17 months after his first cycle.

Results of preoperative neoadjuvant chemotherapy and surgery in the management of patients with soft tissue sarcoma.

Between 1977 and 1991 653 patients were treated for soft tissue sarcoma. Since 1985 limb saving surgery following preoperative neoadjuvant regional chemotherapy has taken place in 53 patients with stage III/A,B disease. In 56.6% (30 patients) treatment was indicated by tumour recurrence. Intra-arterial chemotherapy cycles were performed with doxorubicin (ADM) and cisplatin (cDDP) in the form of rapid infusion. In 25 patients (47%) partial or complete remission (PR,CR) and in 28 patients (53%) minimal response (MR) could be observed. Following neoadjuvant therapy 52 patients underwent limb saving surgery. The patients were followed up for 3-77 months. Due to recurrence, reoperation was required in 22.4% of the cases (11/49 patients). Distant metastases developed in 32.6% (16/49 patients). No intraoperative mortality occurred, the perioperative mortality was 5.7% (three patients).

[Percutaneous balloon-catheter dilatation of benign strictures of the bile ducts]. / A benignus epeúti szükületek percutan ballonkatéteres tágítása.

Two cases of patients with benign biliary strictures (one with anastomotic and another with iatrogen stenosis of the common bile duct) successfully treated by percutaneous transhepatic balloon dilatation are presented. The patients have been symptom-free for 24 and 14 months, respectively. The author deals with the indication of the procedure including all the benign stenoses where surgical reconstruction is not feasible. It is also emphasized that the balloon dilatation needs rather long-time manipulation during which both the patient and the personnel are exposed to significant amount of scattered radiation. One of the important factors in decreasing the need for manipulation is the availability of adequate devices (a series of high pressure balloon catheters).

Neoadjuvant intraarterial chemotherapy of soft tissue sarcomas.

A group of 51 patients with extremity sarcomas of soft-tissue origin received preoperative intraarterial (i.a.) chemotherapy via a percutaneously placed catheter. Treatments were performed as a series of chemotherapy cycles, giving a total of 129, and were carried out in the form of short-term infusions consisting of doxorubicin and cisplatin, which lasted for 20-40 min. These i.a. infusions were combined with complementary methods, such as a tourniquet, occlusion-infusion and chemoembolization. In 3 patients complete remission and in 21 partial remission was registered, while in 27 patients only minimal response could be achieved, although in this latter group necrosis of eight tumors proved to be of significant value. In 43 of 51 patients successful limb salvage surgery was carried out.

Aneurysmal bone cyst. A review of 52 primary and 16 secondary cases.

Authors report on the results of treatment of 52 primary and 16 secondary aneurysmal bone cysts (ABC). ABC grow rapidly; 84% of them have already destroyed more than the half of the bone width at recognition. En bloc resection is preferred when the ABC is growing superficially and eccentrically and more than half of the bone width is intact. Careful curettage and bone grafting still remains the surgical method of choice in the majority of cases, when the ABC is more destructive and affects the subchondral bone of the joints. Segmental resection is only indicated when removal of the affected bone does not influence the function of the extremity. Superselective embolization of the cyst was performed in seven cases with excellent results. This method is suggested for ABC in certain locations inaccessible to surgical intervention, e.g., the pelvis, or to avoid excessive bleeding in hypervascularized tumors. In one case, however, an incomplete rebuilding of the ABC could only be achieved by the administration of calcitonin. The 16 cases of secondary ABC were observed mostly in association with osteoblastomas, giant-cell tumors, and osteosarcomas. The incidence of the secondary ABC was 23% in the whole ABC group but not more than 2-4% among the osteosarcomas and giant-cell tumors. Secondary ABC may confuse the histological and clinical diagnoses and that, especially in cases of osteosarcoma, may have fatal consequences.

Aneurysmal bone cysts treated by superselective embolization.

A series of 7 cases of aneurysmal bone cysts (ABC), all but 1 located in the pelvic bones, which were treated by transcatheter embolization is presented. Five embolizations were performed for primary treatment, while in 2 patients they were performed preoperatively. In all patients a definite histological diagnosis was established by open biopsy, and plain radiographs as well as computerized tomography (CT) were applied for evaluation of the results. The embolizing materials were tissue adhesive for permanent, and Gelfoam for preoperative vessel occlusions. Of 5 lesions treated for the purpose of definitive embolization, 3 (all located in the superior pubic ramus) showed complete ossification; in one, partial remineralization and progression occurred. In a further patient with a secondary ABC, partial reconstitution was recorded. Both preoperative embolizations resulted in successful en bloc resection with minimal blood loss. Transcatheter embolization is the treatment of choice for the highly vascular ABC in unfavorable anatomical locations.