Type-B monoamine oxidase inhibitors in neurological diseases:clinical applications based on preclinical findings

Type-B monoamine oxidase inhibitors,encompassing selegiline,rasagiline,and safinamide,are available to treat Parkinson's disease.These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease.There is also evidence suppo rting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease,such as mood deflection,cognitive impairment,sleep disturbances,and fatigue.Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors,particularly glial cell line-derived neurotrophic factor,which suppo rt dopaminergic neurons.Besides,safinamide may interfere with neurodegenerative mechanisms,countera cting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity.Due to the dual mechanism of action,the new generation of type-B monoamine oxidase inhibitors,including safinamide,is gaining interest in other neurological pathologies,and many supporting preclinical studies are now available.The potential fields of application concern epilepsy,Duchenne muscular dystrophy,multiple scle rosis,and above all,ischemic brain injury.The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline,rasagiline,and safinamide in Parkinson's disease and beyond,focusing on possible future therapeutic applications.

Ketoprofen,peginterferon 2a and ribavirin for genotype 1 chronic hepatitis C:A phaseⅡ study

AIM:To evaluate the safety of adding ketoprofen to pegylated-interferon(PEG-IFN)with or without ribavirin and the effect on viral kinetics,STAT1 activity and expression of 2'-5'-oligoadenylate synthetase (2'-5'OAS)in genotype 1 chronic hepatitis C in a phaseⅡstudy. METHODS:Forty-five patients were studied:fifteen were randomized to PEG-IFN plus ribavirin(PR),16 to PEGIFN plus ketoprofen and 14 to PR and ketoprofen.Themolecular study of IFN-dependent signal transduction was conducted in 9 patients from each group. RESULTS:The combination of ketoprofen and PEG- IFN with or without ribavirin was safe and well tolerated.An early activation of STAT1 was observed in ke-toprofen-treated patients,but this activation was less sustained over time.Conversely,ketoprofen plus PEG- IFN and ribavirin induced an early and sustained increase of 2'-5'OAS transcription starting 24 h after the first dose until the 36th wk.These data are consistent with the clinical results,showing a better sustained virological response and a lower relapse rate in patients receiving ketoprofen plus PEG-IFN and ribavirin. CONCLUSION:The addition of ketoprofen to the standard therapy of chronic hepatitis C should be explored in larger randomized clinical studies.

Multi-modal investigation of the bone micro- and ultrastructure, and elemental distribution in the presence of Mg-xGd screws at mid-term healing stages

Magnesium(Mg)–based alloys are becoming attractive materials for medical applications as temporary bone implants for support of fracture healing,e.g.as a suture anchor.Due to their mechanical properties and biocompatibility,they may replace titanium or stainless-steel implants,commonly used in orthopedic field.Nevertheless,patient safety has to be assured by finding a long-term balance between metal degradation,osseointegration,bone ultrastructure adaptation and element distribution in organs.In order to determine the implant behavior and its influence on bone and tissues,we investigated two Mg alloys with gadolinium contents of 5 and 10 wt percent in comparison to permanent materials titanium and polyether ether ketone.The implants were present in rat tibia for 10,20 and 32 weeks before sacrifice of the animal.Synchrotron radiation-based micro computed tomography enables the distinction of features like residual metal,degradation layer and bone structure.Additionally,X-ray diffraction and X-ray fluorescence yield information on parameters describing the bone ultrastructure and elemental composition at the bone-to-implant interface.Finally,with element specific mass spectrometry,the elements and their accumulation in the main organs and tissues are traced.The results show that Mg-xGd implants degrade in vivo under the formation of a stable degradation layer with bone remodeling similar to that of Ti after 10 weeks.No accumulation of Mg and Gd was observed in selected organs,except for the interfacial bone after 8 months of healing.Thus,we confirm that Mg-5Gd and Mg-10Gd are suitable material choices for bone implants.

High-resolution ex vivo analysis of the degradation and osseointegration of Mg-xGd implant screws in 3D

Biodegradable magnesium(Mg)alloys can revolutionize osteosynthesis,because they have mechanical properties similar to those of the bone,and degrade over time,avoiding the need of removal surgery.However,they are not yet routinely applied because their degradation behavior is not fully understood.In this study we have investigated and quantified the degradation and osseointegration behavior of two biodegradable Mg alloys based on gadolinium(Gd)at high resolution.Mg-5Gd and Mg-10Gd screws were inserted in rat tibia for 4,8 and 12 weeks.Afterward,the degradation rate and degradation homogeneity,as well as bone-to-implant interface,were studied with synchrotron radiation micro computed tomography and histology.Titanium(Ti)and polyether ether ketone(PEEK)were used as controls material to evaluate osseointegration.Our results showed that Mg-5Gd degraded faster and less homogeneously than Mg-10Gd.Both alloys gradually form a stable degradation layer at the interface and were surrounded by new bone tissue.The results were correlated to in vitro data obtained from the same material and shape.The average bone-to-implant contact of the Mg-xGd implants was comparable to that of Ti and higher than for PEEK.The results suggest that both Mg-xGd alloys are suitable as materials for bone implants.

On the material dependency of peri-implant morphology and stability in healing bone

The microstructural architecture of remodeled bone in the peri-implant region of screw implants plays a vital role in the distribution of strain energy and implant stability.We present a study in which screw implants made from titanium,polyetheretherketone and biodegradable magnesium-gadolinium alloys were implanted into rat tibia and subjected to a push-out test four,eight and twelve weeks after implantation.Screws were 4 mm in length and with an M2 thread.The loading experiment was accompanied by simultaneous three-dimensional imaging using synchrotron-radiation microcomputed tomography at 5μm resolution.Bone deformation and strains were tracked by applying optical flow-based digital volume correlation to the recorded image sequences.Implant stabilities measured for screws of biodegradable alloys were comparable to pins whereas non-degradable biomaterials experienced additional mechanical stabilization.Peri-implant bone morphology and strain transfer from the loaded implant site depended heavily on the biomaterial utilized.Titanium implants stimulated rapid callus formation displaying a consistent monomodal strain profile whereas the bone volume fraction in the vicinity of magnesium-gadolinium alloys exhibited a minimum close to the interface of the implant and less ordered strain transfer.Correlations in our data suggest that implant stability benefits from disparate bone morphological properties depending on the biomaterial utilized.This leaves the choice of biomaterial as situational depending on local tissue properties.