Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis

Background

Recent data from animal models of multiple sclerosis (MS) and from a pilot study indicated a possible beneficial impact of statins on MS.

Methodology/Principal Findings

Safety, tolerability and effects on disease activity of atorvastatin given alone or in combination with interferon-beta (IFN-β) were assessed in a phase II open-label baseline-to-treatment trial in relapsing-remitting MS (RRMS). Patients with at least one gadolinium-enhancing lesion (CEL) at screening by magnetic resonance imaging (MRI) were eligible for the study. After a baseline period of 3 monthly MRI scans (months −2 to 0), patients followed a 9-month treatment period on 80 mg atorvastatin daily. The number of CEL in treatment months 6 to 9 compared to baseline served as the primary endpoint. Other MRI-based parameters as well as changes in clinical scores and immune responses served as secondary endpoints. Of 80 RRMS patients screened, 41 were included, among them 16 with IFN-β comedication. The high dose of 80 mg atorvastatin was well tolerated in the majority of patients, regardless of IFN-β comedication. Atorvastatin treatment led to a substantial reduction in the number and volume of CEL in two-sided multivariate analysis (p = 0.003 and p = 0.008). A trend towards a significant decrease in number and volume of CEL was also detected in patients with IFN-β comedication (p = 0.060 and p = 0.062), in contrast to patients without IFN-β comedication (p = 0.170 and p = 0.140). Immunological investigations showed no suppression in T cell response but a significant increase in IL-10 production.

Conclusions/Significance

Our data suggest that high-dose atorvastatin treatment in RRMS is safe and well tolerated. Moreover, MRI analysis indicates a possible beneficial effect of atorvastatin, alone or in combination with IFN-β, on the development of new CEL. Thus, our findings provide a rationale for phase II/III trials, including combination of atorvastatin with already approved immunomodulatory therapy regimens.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00616187","term_id":"NCT00616187"}}NCT00616187     

Xiamycin,a pentacyclic indolosesquiterpene with selective anti-HIV activity from a bacterial mangrove endophyte

A novel pentacyclic indolosesquiterpene, named xiamycin (1), and its methyl ester (2) have been obtained from Streptomyces sp. GT2002/1503, an endophyte from the mangrove plant Bruguiera gymnorrhiza. The structures were established by 1D and 2D NMR, MS, and X-ray crystallography, and the absolute configuration of 1 was elucidated by the modified Mosher method. Compound 1 exhibits selective anti-HIV activity; it specifically blocks R5 but has no effects on X4 tropic HIV-1 infection. In a panel of cytotoxicity assays, compound 2 showed to be more potent (geometric mean IC₅₀ = 10.13 μM) compared to compound 1 (geometric mean IC₅₀ >30 μM), with antitumor potency being generally less pronounced. Xiamycin represents one of the first examples of indolosesquiterpenes isolated from prokaryotes.     

Addition reactions at the 16(17) double bond of 3-methoxy-13alpha-estra-1,3,5(10),16-tetraene

The epoxidation, the addition of hypobromous acid, and the hydroboration of 3-methoxy-13alpha-estra-1,3,5(10),16-tetraene 1 with diborane, catecholborane, and 9-BBN were investigated in order to determine the stereochemical outcome and to synthesize new 13alpha-estra-1,3,5(10)-trienes for biological and conformational investigations. It was shown that the sterically demanding reagent 9-BBN participated in a preferred beta attack (53% 16betaOH 10, 34% 17betaOH 8, 13% 16alphaOH 11). This stereochemical result is in agreement with that from another cis addition reaction, the recently described OsO4 dihydroxylation of 1 [Steroids 68 (2003) 113]. With smaller reagents such as B2H6, catecholborane, or magnesium monoperoxyphthalate, a diminished stereoselectivity was observed with only a slight excess of beta attack. The ionic trans addition of hypobromous acid gave two 17-bromo-16-alcohols with 16beta,17alpha (4, 76%) and 16alpha,17beta configuration (5, 24%) formed by trans cleavage of the 16,17alpha- and beta-bromonium ion at position 16. The same regioselective and stereoselective course was found for the cleavage of the 16alpha,17alpha- and 16beta,17beta-epoxides (3 and 2) with hydrazoic acid (3-->16betaN3,17alphaOH 7, 2-->16alphaN3,17betaOH 6). The stereochemistry of the addition reactions to 1 can be explained in terms of a twist-boat conformation involving the C ring of compound 1. From a synthetic viewpoint the synthesis of the beta-epoxide 2 from the bromohydrin 4, the cleavage of this epoxide to 16alpha-substituted-17beta-hydroxy compounds, such as 6, and hydroboration/oxidation with 9-BBN to the hitherto unknown 16beta-hydroxy compound 10 are useful procedures. The bromohydrin 5 is the first 13alpha-steroid with a 17beta-bromo substituent. X-ray analysis revealed twist-boat and 16beta-envelope conformations for rings C and D, respectively.     

Dimeric phenylphenalenones from Musa acuminata and various Haemodoraceae species. Crystal structure of anigorootin

Three fused octacyclic phenylphenalenone dimers were isolated from Musa acuminata: Anigorootin, which was first isolated from Anigozanthos flavidus and hitherto represented the only compound of that type, the new 4'-hydroxy-anigorootin, and 4',4"-di-hydroxy-anigorootin, which is a revised structure. The crystal structure of anigorootin was determined by X-ray crystallography. 3,3'-Bis-hydroxyanigorufone, a dimer of the conventional type known from Anigozanthos preissii, was also found in Musa acuminata. Phytochemical analysis of several Haemodoraceae species revealed the occurrence of anigorootin, 3,3'-bis-hydroxyanigorufone, and the novel metabolite 3,3'-bis-anigorufone. The occurrence of the same compounds in Musaceae and Haemodoraceae indicates the close chemotaxonomic relationship of both plant families.     

Synthesis,structure and catechol-oxidase activity of copper(II) complexes of 17-hydroxy-16-(N-3-oxo-prop-1-enyl)amino steroids

Copper is next to iron the most important element in the biological transport, storage and in redox reactions of dioxygen. A bioanalogous activation of dioxygen with copper complexes is used for catalytical epoxidation, allylic hydroxylation and oxidative coupling of aromatic substrates, for example. With stereochemical information in form of chiral ligands, enantioselective reactions may be possible. Another aspect of interest on copper catalyzed reactions with dioxygen is that the exact mechanism and biological function of some enzymes (especially catechol oxidase) is yet not fully clear. For studies mimicking the copper-containing catechol oxidase appropriate chiral steroid ligands with defined stereochemistry and conformation have been synthesized. The four diastereomeric 16,17-aminoalcohols of the 3-methoxy-estra-1,3,5(10)-triene series have been condensed with salicylic aldehyde and different beta-ketoenols to the chiral ligand types 1-5. These compounds with different steric and electronic properties and different arrangements of the neighboring hydroxy and nitrogen functions were reacted with copper(II) acetate to copper complexes. The structure of these complexes will be discussed. The bioanalogous oxidation of 3,5-di-tbutyl-catechol (dtbc) to the corresponding quinone was catalyzed by most of the complexes, indicating their ability to activate dioxygen. The trans configurations c and d showed an activity one magnitude higher than the cis configurations a and b. Comparing compounds with the same diastereomeric configuration, the main influence was that of the peripheral R(1-3) substituents at the beta-ketoenaminic group which are useful for the fine-tuning of the properties of the copper atoms like redox potential and Lewis acidity.     

Oxidations of sulfur rich heterocycles - new S-oxides of the parent 1,2,4-trithiolane and its tetramethyl derivative: synthesis and structural investigations

Whereas oxidation of 1,2,4-trithiolane (1) with 1 molar equiv. of m-chloroperbenzoic acid (mCPBA) yielded 1,2,4-trithiolane 4-oxide (3) and a small amount of 1,2,4-trithiolane 1-oxide (2), the reaction with 2.5 molar equiv. of mCPBA afforded exclusively 1,2,4-trithiolane 1,4-dioxide (trans-7). The oxidation of 3,3,5,5-tetramethyl-1,2,4-trithiolane (4) with peroxyacetic acid (1 molar equiv. H₂O₂/AcOH) gave a mixture of regioisomeric 3,3,5,5-tetramethyl-1,2,4-trithiolane 4-oxide (6) as a major product and only traces of 1-oxide 5. Using 2.5 molar equiv. of peroxyacetic acid in reaction with 4 a mixture of both stereoisomers of 3,3,5,5-tetramethyl-1,2,4-trithiolane 1,4-dioxides cis-8 and trans-8 was isolated. Furthermore, 4 was oxidized to 3,3,5,5-tetramethyl-1,2,4-trithiolane 1,1,4,4-tetraoxide (9) using 6 molar equiv. of peroxyacetic acid. The molecular structures of 3, trans-7, trans-8 and 9 were unambiguously established by X-ray structure analysis. Compounds 1-4, trans-7, trans-8 and 9 were investigated by Raman spectroscopy. Ab initio calculations were used to obtain the optimized geometries and the vibrational wavenumbers of the title compounds. The vibrational assignment was accomplished by using the calculated harmonic wavenumbers and their Raman intensities. The calculated values of both structural parameters and the vibrational modes fitted in with experimental data. The spectroscopic changes observed in the spectra were correlated with the structural parameters in order to gain information about the influence of the oxidation on the molecule structure. The experimental data indicated, that in comparison with starting 1,2,4-trithiolanes 1 and 4 their oxidized derivatives showed remarkable shortening of the S-S bonds.     

Chromatographic separation of vitamins D2 and D3 and related compounds

A reversed-phase chromatographic system is described that is capable of separating vitamin D₂ from vitamin D₃ and ergosterol from 7-dehydro-cholesterol and cholesterol. The method uses Factice, a polymerized and vulcanized soybean oil, as stationary phase and a water/acetone mitxure as mobile phase. In contrast to other previously published techniques capable of separating vitamins D₂ and D₃, the present separation is accomplished without any chemical modification or alteration of the D-vitamins.     

Quinpramine ameliorates rat experimental autoimmune neuritis and redistributes MHC class II molecules

Activation of inflammatory cells is central to the pathogenesis of autoimmune demyelinating diseases of the peripheral nervous system. The novel chimeric compound quinpramine--generated from imipramine and quinacrine--redistributes cholesterol rich membrane domains to intracellular compartments. We studied the immunological and clinical effects of quinpramine in myelin homogenate induced Lewis rat experimental autoimmune neuritis (EAN), a model system for acute human inflammatory neuropathies, such as the Guillain-Barré syndrome. EAN animals develop paresis of all limbs due to autoimmune inflammation of peripheral nerves. Quinpramine treatment ameliorated clinical disease severity of EAN and infiltration of macrophages into peripheral nerves. It reduced expression of MHC class II molecules on antigen presenting cells and antigen specific T cell proliferation both in vitro and in vivo. Quinpramine exerted its anti-proliferatory effect on antigen presenting cells, but not on responder T cells. Our data suggest that quinpramine represents a candidate pharmaceutical for inflammatory neuropathies.     

Novel trigonal prismatic iron complexes of expanded hexadentate Jäger type ligands: synthesis and X-ray analysis

The mononuclear iron complexes Fe2a and Fe2b of expanded hexadentate Jäger type ligands H₃2a and H₃2b with [N₄O₂]-donorset were synthesized via reaction of the free ligands with iron(II) acetate. The identity of both compounds was proven by mass spectrometry and micro analysis. Furthermore crystals suitable for X-ray structure determination were obtained in case of Fe2a. The X-ray investigation reveals that this compound is a hexacoordinated iron complex with a rather rare trigonal prismatic geometry of the coordination polyeder: in this complex all six coordination sites are occupied by the donor atoms of the ligand exclusively, which was observed for the first time in iron complexes of Jäger type ligands. Electronic properties of Fe2b were characterized using EPR-spectroscopy and temperature dependent susceptibility measurements, indicating a high-spin Fe(III) complex.     

Short-term effect of ammonia on nitrogenase activity of Anabaena variabilis (ATCC29413)

Abstract Intact filaments of the cyanobacterium Anabaena variabilis switch off nitrogenase activity very rapidly upon addition of NH₄Cl when incubated in an alkaline environment (pH 10.0) permitting a fast NH₃-influx into the cells. When assayed in cell-free extracts (prepared from ammonia-treated filaments), nitrogenase remains inhibited in the presence of an ATP-regenerating system. Furthermore, l -methionine- d,l -sulfoximine, an inhibitor of glutamine synthetase, added to the filaments, prevents inactivation of nitrogenase by ammonia, showing that ammonia is not the compound directly responsible for nitrogenase switch-off.