Matching-adjusted comparisons demonstrate better clinical outcomes in patients with relapsing multiple sclerosis treated with peginterferon beta-1a than with teriflunomide.

BACKGROUND: Peginterferon beta-1a and teriflunomide are both first-line disease-modifying therapies (DMTs) approved for the treatment of relapsing multiple sclerosis (RMS); however, no head-to-head trials have directly compared their clinical efficacy. We performed a matching-adjusted comparison of individual patient data from the peginterferon beta-1a pivotal phase 3 study, ADVANCE, and its extension study, ATTAIN, with pooled aggregated data from the teriflunomide pivotal phase 3 studies, TEMSO and TOWER. METHODS: A total of 512 patients randomized to subcutaneous (SC) peginterferon beta-1a 125 mcg every 2 weeks in ADVANCE and 731 patients randomized to teriflunomide 14 mg daily (359 from TEMSO and 372 from TOWER) were matched on key baseline characteristics. After matching, weighted annualized relapse rate (ARR) and 24-week confirmed disability worsening (CDW) were calculated and compared for peginterferon beta-1a- and teriflunomide-treated patients. A subset analysis comparing weighted ARR in patients who were newly diagnosed with RMS (diagnosis ≤1 year before study enrollment and disease-modifying therapy naïve) was also performed. RESULTS: After matching, the peginterferon beta-1a and teriflunomide treatment groups were identically matched across baseline characteristics. The proportion of patients in the overall study populations with 24-week CDW at 108 weeks was significantly lower in the peginterferon beta-1a group than the teriflunomide group both before matching (8.5% vs 12.6%; P = 0.0249) and after matching (8.4% vs 12.6%; P = 0.0323). ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide both before matching (0.278 vs 0.354; P = 0.1326) and after matching (0.257 vs 0.354; P = 0.0510). Newly diagnosed patients treated with peginterferon beta-1a had numerically lower ARR than patients treated with teriflunomide both at 108 weeks (before matching: 0.225 vs 0.270; P = 0.587; after matching: 0.201 vs 0.270; P = 0.384) and at 5 years (before matching: 0.150 vs 0.196; after matching: 0.142 vs 0.196). CONCLUSIONS: In this matching-adjusted comparison of patients with RMS from three phase 3 trials, a significantly lower proportion of patients treated with SC peginterferon beta-1a 125 mcg every 2 weeks than with oral teriflunomide 14 mg once daily had 24-week CDW at 108 weeks. In addition, in both the overall population and newly diagnosed patient subgroups, ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide. The numerically lower ARR in newly diagnosed patients treated with peginterferon beta-1a compared with those treated with teriflunomide was sustained through up to 5 years of treatment.

Facile functionalization of Teriflunomide-loaded nanoliposomes with Chondroitin sulphate for the treatment of Rheumatoid arthritis.

This research aims to coat Teriflunomide (TEF) loaded conventional nanoliposomes (CON-TEF-LIPO) with Chondroitin sulphate (CS) to produce CS-TEF-LIPO for the effective treatment of Rheumatoid arthritis (RA). Both CON-TEF-LIPO and CS-TEF-LIPO were produced, characterized and evaluated for their active targeting potential towards CD44 receptors. Cell cytotoxicity, cell viability and intracellular uptake study on differentiated U937 and MG-63 cells demonstrated the active targeting of CS-TEF-LIPO towards CD44 receptors. Furthermore, in vivo pharmacodynamic, biochemical, radiological and histopathological studies performed in adjuvant induced arthritic (AIA) rat model showed a significant (P < 0.05) reduction in inflammation in arthritic rat paw in CS-TEF-LIPO group compared to TEF and CON-TEF-LIPO groups. Moreover, liver toxicity study revealed that CS-TEF-LIPO showed no signs of toxicity and biodistribution study revealed the accumulation of CS-TEF-LIPO in synovial region of arthritic rat. Taken together, results suggest that CS-TEF-LIPO could provide a new insight for an effective treatment of RA.

Synthesis and properties of cyclic acetal biomaterials.

There is an increasing need to develop new biomaterials as tissue engineering scaffolds. Unfortunately, many of the materials that have been studied for these purposes are polyesters that hydrolytically degrade into acidic products, which may harm the surrounding tissue, and lead to accelerated degradation of the biomaterial. To overcome this disadvantage, a novel class of biomaterials based on a cyclic acetal unit has been created. Specifically, materials based upon the monomer 5-ethyl-5-(hydroxymethyl)-beta,beta-dimethyl-1,3-dioxane-2-ethanol diacrylate (EHD) is examined. This study investigates the effects of fabrication parameters, including initiator content, volume of diluent, and volume of accelerant, on several properties of EHD networks. Twelve different formulations were fabricated by varying the three parameters in a factorial design. The effects of the fabrication parameters on properties of the EHD networks were examined. Results show that the volume of accelerant most affected the EHD network gelation time, while the volume of diluent most affected the maximum reaction temperature, sol fraction, and degree of swelling. Cell viability on the EHD networks varied between (18 +/- 6)% and (57 +/- 10)% of the control at 4 h, and between (36 +/- 14)% and (140 +/- 50)% of the control at 8 h. These results indicate that it is possible to control the properties of the EHD networks by varying the fabrication parameters, and that EHD networks support a viable cell population.

Radicals produced by blue-light-resin interactions alter the redox status of THP1 human monocytes.

Resin composites are widely used in dentistry, and are polymerized in situ using a blue-light activated, free-radical polymerization mechanism. Blue light (400-500nm) is used to activate camphoroquinone (CQ), which decomposes to form free radicals that are stabilized by dimethyl-p-toludine (DMPT). CQ and DMPT are applied near tooth pulpal tissues and are irradiated during restorative procedures, suggesting that pulpal cells are exposed to free radicals. Because glutathione is a major component of the cellular redox management system, we tested the hypothesis that blue light irradiation would shift cellular glutathione redox balance of cells exposed to CQ and DMPT. We also measured NFkappaB activation, a redox-sensitive transcription factor that regulates inflammatory responses and glutathione synthetic enzyme levels. THP1 human monocytes were exposed to sublethal levels of CQ (0.4 mM) or DMPT (1.0 mM), with or without blue light exposure (25 J/cm(2)) from a quartz-tungsten-halogen source. The ratio of reduced to oxidized glutathione was measured using as assay based on 5,5'-dithio-bis(2-nitrobenszoic acid). NFkappaB transactivation was measured by transfection of an NFkappaB-containing plasmid linked to a luciferase reporter. Our results showed that blue light, CQ, or DMPT alone had no significant effect on cellular glutathione redox balance, but that the combination of these agents induced a marked oxidative bias, and reduced total glutathione levels up to 50%. On the other hand, light, CQ, and DMPT alone or in combination suppressed NFkappaB transactivation by >70%. Our results suggest that CQ and DMPT pose risks to pulpal tissues with or without blue light irradiation, and that multiple, interacting mechanisms shape the response to these agents.

Preparation and characterization of polymeric coatings with combined nitric oxide release and immobilized active heparin.

A new dual acting polymeric coating is described that combines nitric oxide (NO) release with surface-bound active heparin, with the aim of mimicking the nonthrombogenic properties of the endothelial cell (EC) layer that lines the inner wall of healthy blood vessels. A trilayer membrane configuration is employed to create the proposed blood compatible coating. A given polymeric substrate (e.g., the outer surface of a catheter sleeve, etc.) is first coated with a dense polymer layer, followed by a plasticized poly(vinyl chloride) (PVC) or polyurethane (PU) layer doped with a lipophilic N-diazeniumdiolate as the NO donor species. Finally, an outer aminated polymer layer is applied. Porcine heparin is then covalently linked to the outer layer via formation of amide bonds. The surface-bound heparin is shown to possess anti-coagulant activity in the range of 4.80-6.39 mIU/cm2 as determined by a chromogenic anti-Factor Xa assay. Further, the surface NO flux from the underlying polymer layer containing the diazeniumdiolate species can be controlled and maintained at various levels (from 0.5 to 60 x 10(-10) mol cm(-2)min(-1)) for at least 24 h and up to 1 week (depending on the flux level desired) by changing the chemical/polymer composition of the NO release layer. The proposed polymeric coatings are capable of functioning by two complementary anti-thrombotic mechanisms, one based on the potent anti-platelet activity of NO, and the other the result of the ability of immobilized heparin to inhibit Factor Xa and thrombin (Factor IIa). Thus, the proposed polymeric coatings are expected to exhibit greatly enhanced thromboresistivity compared to polymers that utilize either immobilized heparin or NO release alone.

Characterization of an injectable, degradable polymer for mechanical stabilization of mandibular fractures.

This study investigated the use of injectable poly(propylene fumarate) (PPF) formulations for mandibular fracture stabilization applications. A full factorial design with main effects analysis was employed to evaluate the effects of the PPF:N-vinyl pyrrolidone (NVP, crosslinking agent) ratio and dimethyl toluidine (DMT, accelerator) concentration on key physicochemical properties including setting time, maximum temperature, mechanical properties, sol fraction, and swelling ratio. Additionally, the effects of formulation crosslinking time on the mechanical and swelling properties were investigated. The results showed that increasing the PPF:NVP ratio from 3:1 to 4:1 or decreasing the DMT concentration from 0.05 to 0.01 v/w % significantly decreased all mechanical properties as well as significantly increased the sol fraction and swelling ratio. Also, increasing the crosslinking time at 37°C from 1 to 7 days significantly increased all mechanical properties and decreased both the sol fraction and swelling ratio. This study further showed that the flexural stiffness of ex vivo stabilized rabbit mandibles increased from 1.7 ± 0.3 N/mm with a traditional mini-plate fixator to 14.5 ± 4.1 N/mm for the 4:1 (0.05 v/w % DMT) PPF formulation at day 1. Overall, the formulations tested in this study were found to have properties suitable for potential further consideration in mandibular fracture fixation applications.

The effects of current dentinal adhesives on the dentinal surface.

The effects of the dentinal surface treatments from six currently available commercial dentinal adhesives are presented. The adhesives are All-Bond 2, etched and unetched, Syntac, Prisma Universal Bond 3, Scotchbond Multipurpose, Tenure Solution, and Adhesive By Choice. Unerupted third molar human teeth were sectioned and treated with the appropriate adhesive according to the manufacturer's directions. After the teeth were treated, they were processed for observation by scanning electron microscopy. Scanning-electron microscopic photomicrographs were made of each step in the process to show the effects of the constituents, including the adhesives, on the dentinal surface. For All-Bond 2, unetched, the smear layer was not removed before the primer and the adhesive were applied. The primer for Prisma Universal Bond 3 altered the smear layer by reacting with it but did not produce a large demineralized zone in the dentin. All the other adhesives did remove the smear layer before the tooth was treated with the primer and adhesive.

Durability of the bond between bone and various 2-cyanoacrylates in an aqueous environment.

The durability of the bond strength developed between 2-cyanoacrylate esters and bone has been determined by aging specimens in water. One-day bond strength of the isobutyl and isomeric amyl 2-cyanoacrylates varied from 6.2 to 7.2 MPa. The strength of the bond decreased on storage or on thermocycling in water. Hydrolytic stability increased with increasing length of the alkyl ester group. After a six-month storage in water the various amyl 2-cyanoacrylates retained from 70% to 73% of their one-day bond strength. Pretreatment of the bone surface prior to application of the adhesive did not prove beneficial. The cured 2-cyanoacrylate can be removed from the substrate surface by appropriate solvents. Thus, it is not bonded covalently to bone. The bond strength, especially of the isobutyl and amyl 2-cyanoacrylates to bone in an aqueous environment, appears to be superior to other adhesives. Provided these monomers are biocompatible, they may be useful clinically where an intermediate-term adhesion is desired.

Intradermal study of a new local anaesthetic agent aptocaine.

In a double-blind trial in 28 human volunteers, a new local anaesthetic agent, aptocaine, was compared intradermally at 1, 2 and 3% concentrations with lignocaine 2% and bupivacaine 0.5%. In a second trial in 27 subjects, 1% aptocaine was compared with mepivacaine and prilocaine, both 1, 2 and 3%. In terms of activity as determined by area of anaesthesia, and of duration of action, aptocaine was similar to mepivacaine and more active and long-lasting than lignocaine and prilocaine. By this route aptocaine also appeared longer-lasting than bupivacaine. Duration of action was unaffected by concentration. Aptocaine had marked vasoconstrictor activity, which was maximal at 1%. These local anaesthetic properties suggest that aptocaine merits clinical trials, especially in dentistry.

[New antihypertensive agent of the imidazoline series: 5-fluoro-methyl-imidazolidinylidene-benzamine-monohydrochloride (flutonidin)]. / Ein neues Antihypertensivum der Imidazolinreihe: 5-Fluor-2-methyl-imidazolidinyliden-benzamin-monohydrochlorid (Flutonidin).

A New Antihypertensive of the Imidazoline Series: 5-Fluoro-2-methyl-imidazolidinylidene-benzamine-monohydrochloride. 5-Fluoro-2-methyl-imidazolidinylidene-benzamine-hydrochloride (flutonidin, ST 600), a new antihypertensive imidazoline compound, was tested over 3 weeks in 20 patients with moderate to severe hypertension. Blood pressure was significantly lowered in both supine and upright position. In nearly 2/3 of the patients treated normalization of blood pressure was achieved. Side effects like sedation, dry mouth or orthostatic complaints were present in 30%. Toxic effects were not registered. It is recommended to reduce the dosage slowly especially in the aged to prevent, in part severe findings after abrupt withdrawal.

[The sensitivity of various in-vitro-test systems in biological testing of materials]. / Uber die Empfindlichkeit verschiedener In-vitro-Testsysteme bei der biologischen Materialpruüfung.

In the present paper the biological activity of methylmethacrylate Monomer and di-methylparatoluidin on stationary, cell-proliferating and bacterial cultures is examined. The equi-toxic concentrations were lower in cell culture systems than in stationary cell suspensions or bacterial cultures. Accordingly biological reaction appears to depend on the effective concentration of the toxic substance as well as on the specific sensitivity of the test system. There is no correlation between the sensitivity of cellular and of bacterial test systems.

The relationship between leachability of polymerization initiator and degree of conversion of visible light-cured resin.

Recently, polymerization-initiator-induced radicals have been identified as a biohazard as well as residual monomers. The present investigation was conducted to clarify the leaching behavior of the polymerization initiator and to measure the relationship between the leached amount of polymerization initiator and the degree of conversion of visible light (VL)-cured resin. Moreover, determining a suitable ratio of polymerization initiator to the base monomer according to the above relationship was carried out. The base monomer (UDMA/TEGDMA) was activated with varying concentrations of polymerization initiator (CQ/DMPT, CQ/DMAEMA) from 0.3-0.9 wt%, respectively, which were exposed to light for 40 s. Gas chromatograph mass spectrometry (GCMS) was carried out to evaluate the leached amount of polymerization initiator. The degree of conversion (DC) of the cured sample was estimated using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. As the result, it was recognized that the leachability of the polymerization initiator (CQ, DMPT, and DMAEMA) depended on the degree of conversion of the VL-cured resin. Therefore, the optimal concentration of polymerization initiator can be determined from the relation between the degree of conversion and the leached amount of polymerization initiator, which is about 0.6 wt% for CQ/DMPT (1:1 in weight) and 0.5 wt% for CQ/DMAEMA (1:1 in weight) relative to the UDMA/TEGDMA (1:1 in weight) monomer.

Hypotensive action and side-effects of flutonidin in normal subjects. A double-blind controlled trial.

In a double blind study, planned as a 7 x 7 latin square, three oral doses of flutonidin (0.5, 1, 2 mg), of clonidine (0.0075, 0.150, 0.300 mg) and of a placebo were administered to 7 normal volunteers on 7 different treatment days, with an interval of 3 days. On each treatment day sitting blood pressure, heart rate and reaction time were measured, and sedation and dry mouth evaluated before the 1, 2, 3, 4, 6, and 8 h after administration. The placebo did not modify the basal value of any variable. Flutonidin and clonidine produced dose-related effects on blood pressure, heart rate, sedation and dry mouth, but did not influence reaction time. Analysis of the dose-response curves demonstrated that the effect of flutonidin was one-fifth to one-twelfth that of clonidine, depending on which variable was considered.

Impact of components of denture acrylic resin on gingival cell growth and sensitivity to Candida albicans adhesion.

The effects of four liquid components of denture acrylic resin on host cell activity and fungal adhesion were investigated in this study. The low concentration (1 micromol l(-1)) of the liquid components caused no change in the activities and morphologies of the gingival fibroblast cells, compared with control and dimethylsulphoxide-exposed cells. However, when the cells were exposed to high concentrations (1 mmol l(-1)) of benzqyl peroxide, morphological change was observed, implying that the exposure of the cells to high concentrations of the liquid components of denture acrylic causes the loss of adhesion proteins from the cells. Thus the amount of Candida adhesion to human gingival cells was analysed, and the adherence of fungi to the cell was significantly reduced when the cells were pre-exposed to methyl methacrylate, hydroquinone and benzoyl peroxide at a concentration of 1 micromol l(-1) (P < 0.01), which did not affect either the cell viability or the cell morphology. These results, taken together, suggested that the renewal of dentures could be a possible therapeutic and/or preventive aid for oral candidosis in denture-wearing patients.

Amitraz effects on foot-and-mouth disease virus in mammalian cells in vitro.

The toxicity of the acaricide amitraz and its effect on foot-and-mouth disease virus multiplication were evaluated in IB-RS-2 cells in vitro. A reduction of cell growth rate that was dependent on the dose and the length of treatment was observed in cells exposed to amitraz concentrations ranging from 20 to 50 micrograms/ml. Foot-and-mouth disease virus infectivity remained essentially unchanged in cells exposed to amitraz (20 micrograms/ml) 24 hr prior to virus infection or after the adsorption period. Viral RNA synthesis evaluated through [3H]uridine incorporation in cells treated for 24 hr prior to infection was not affected by amitraz.