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Introduction: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. Methods: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. Results: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR+ patients there was a trend toward increased malignancy (P = 0.15). Conclusions: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA-DR11.

Introduction: Inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) with statins may trigger idiopathic inflammatory myositis (IIM) or immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR antibodies have been detected in patients with IIM/IMNM. We aimed to determine the associations of anti-HMGCR in IIM/IMNM. Methods: Anti-HMGCR antibodies were detected by ELISA in sera from patients with IIM/IMNM. Results: Anti-HMGCR antibodies were detected in 19 of 207 patients with IIM/IMNM, and there was a trend toward an association with male gender (P = 0.079). Anti-HMGCR antibodies were associated strongly with statin exposure (OR = 39, P = 0.0001) and HLA-DRB1*11 (OR = 50, P < 0.0001). The highest risk for development of anti-HMGCR antibodies was among HLA-DR11 carriers exposed to statins. Univariate analysis showed a strong association of anti-HMGCR antibodies with diabetes mellitus (P = 0.008), which was not confirmed by multiple regression. Among anti-HMGCR+ patients there was a trend toward increased malignancy (P = 0.15). Conclusions: Anti-HMGCR antibodies are seen in all subtypes of IIM and IMNM and are associated strongly with statin use and HLA-DR11.

Thiol- or acid-promoted additions of silyl radicals to camptothecin are reported. At 105°C, mixtures of 7-silyl (favored) and 12-silyl camptothecins are formed alongside substantial amounts of recovered camptothecin. At 160°C, 12-silyl isomers are formed preferentially, but the total mass balance is substantially reduced. The silyl radical addition is featured in short semi-syntheses of DB-67 (7-tert-butyldimethylsilyl-10-hydroxy camptothecin) from both camptothecin and 10-hydroxycamptothecin. © 2002 Elsevier Science Ltd. All rights reserved.

Thiol- or acid-promoted additions of silyl radicals to camptothecin are reported. At 105°C, mixtures of 7-silyl (favored) and 12-silyl camptothecins are formed alongside substantial amounts of recovered camptothecin. At 160°C, 12-silyl isomers are formed preferentially, but the total mass balance is substantially reduced. The silyl radical addition is featured in short semi-syntheses of DB-67 (7-tert-butyldimethylsilyl-10-hydroxy camptothecin) from both camptothecin and 10-hydroxycamptothecin. © 2002 Elsevier Science Ltd. All rights reserved.

Nemaline myopathies are diseases characterized by the presence in muscle fibres of pathognomonic rod bodies. These are composed largely of alpha−actinin and actin. We have identified a missense mutation in the alpha−tropomyosin gene, TPM3, which segregates completely with the disease in a family whose autosomal dominant nemaline myopathy we had previously localized to chromosome 1p13−q25. The mutation substitutes an arginine residue for a highly conserved methionine in a putative actin−binding site near the N terminus of the alpha−tropomyosin. The mutation may strengthen tropomyosin − actin binding, leading to rod body formation, by adding a further basic residue to the postulated actin−binding motif.

The purpose of the program is to provide chemical compounds for the U.S. Army Medical R and D Command. In the 3.7 years, a total of 27 compounds were delivered in 31 lots. Of these, 26 were targets (30 lots) and one was an intermediate. The targets included five dialkyltetrasulfides, one bisquaternary dioxime, a phosphinylpentanoic acid, thiotaurine and the sodium salt, homothiotaurine, glutathione monoethyl ester, 8-chlorocaprylic acid, and fourteen 8-aminoquinolines. The 8-aminoquinolines included three potential metabolites of WR 238605 and four metabolate acetates as well as one metabolite and three metabolate acetates of WR 242511. 8-Aminoquinoline, Antimalarials, Metabolites, Dialkyltetrasulfide, Bisquaternary pyridinealdoxime, Thiotaurine, Glutathione, Phosphinylpentanoic acid, Synthesis.

The purpose of this contract is to provide chemical compounds for the U.S. Army Medical R and D Command. In the 12 months, five assignments were completed. Compounds submitted include a phosphinylpentanoic acid, an 8-aminoquinoline intermediate and three potential metabolites of WR 238605. Preparative work on a large, 2.5 kg lot of WR 238605 was completed also and analysis and characterization of the final product is in progress. 8-Aminoquinoline, Antimalarials, Metabolites, Phosphinylpentanoic acid, Synthesis, RA 5.

The program was directed at the design and synthesis of treatment and prophylactic drugs as potential defenses against organophosphorus poisoning. During the past 5.5-year period, 81 compounds were submitted; 20 organophosphonates, 13 carbamates, 12 2-oxo-1,3,2-dioxaphosphorinanes, 7 oximes, 4 organophosphonates, one organophosphate, one phosphonothioate, one phosphinothioate, 4 alkythiosulfonic acids, 2 chloroalkyl (aryl) carboxylic acids, suberyldicholine, and 15 other organic compounds.

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No abstract available

The program is directed at the design and synthesis of treatment and prophylactic drugs as potential defenses against organophosphorus poisoning. During the past year, 23 compounds were submitted: three organophosphonates, eight carbamates, one organophosphinic acid, two sadium alkylthiosulfonates, thiosulfonates, thiotaurine, and homothiotaurine, cis-4-chlorobuten-1-o1 and 4- chlorobutanol, one alkylaryl disulfide, two chloroalky(aryl) carboxylic acids, 1,3,5-tris-2'-chloroethylbenzene and d8-thiodiglycol.

The program is directed at the design and synthesis of treatment and prophylactic drugs as potential defenses against organophosphorus poisoning. During the past year, 11 compounds were submitted: one organophosphate; organophosphate; one physostigmine analog; 3-PAM iodide; one perfluoroalkyl alkyl hydroxylamine; one bis(pyridinyl)urea quaternary salt; two 1,3,4- oxadiazolones; one hydroxyimino-3-methylimidazolium salt; one propanesulfonate; and one 4,4-biphenylene-bis(morpholine). Keywords: Organophosphorus poisons, AChE reactivators, Oximes, Hydroxylamines, Carbamates, Synthesis.

The purpose of this contract is to provide chemical compounds for the U.S. Army Medical R & D Command. In the 12 months, 7 assignments were completed. Compounds submitted included a substituted 8-nitroquinoline, five dialkyltetrasulfides and a bisquaternary dioxime. Keywords: 8-Nitroquinoline, Dialkyltetrasulfide, Organic compounds, Bisquaternary pyridinealdoxime, Synthesis, Organic compounds, Chemistry. (js)

The program is directed at the design and synthesis of candidate treatment of prophylactic drugs as potential defenses against organophosphorus poisoning. During the past year, nine compounds were submitted: four organophosphinates, one organophosphonate, one quaternary pyridine, one tropane ester, one (new) physostigmine analoge, and 5-nonanone oxime.

The program is directed at the design and synthesis of new compounds for use in the management of organophosphorus poisoning. In the past three years, 48 compounds were submitted: 26 organophosphinates, one organophosphinothioate, 2 organophosphonates, 2 organophosphates, one oxophospholane, 7 carbamates, 2 sugar oximes, 2 aminoalkylselenic and selonic acids and five other organic compounds. Keywords: Organophosphates; Carbamates; Prophylactics; Therapeutics; Antidotes.

The program is directed at the design and synthesis of new compounds for use in the management of organophosphorus poisoning. In the past year 16 compounds were submitted for evaluation: 11 organophosphinates, two aryl N-methoxy-N-methylcarbamates, a pyridinium carbamate and two sugar oximes, L-rhamnose oxime and D-digitoxose oxime.

This program is directed at the design and synthesis of new compounds for use in the management of organophosphorus poisoning. In the past year 14 compounds were submitted for evaluation: nine organophosphinates, one oxophospholane, two aryl N-hydroxy-N-methycarbamates, one piperidine and one dialkylaminoalkyl glycolate ester.

The program is directed at the design and synthesis of candidate treatment or prophylactic drugs as potential defense against organophosphorus poisoning. During the past year, 17 compounds were submitted: 7 organophosphates, 4 organophosphates, one carbamate, one pyridinealdoxime, one phosphinothioate, one phosphonothioate, one tropate ester and one tetraalkylammonium iodide. Keywords: Synthesis(chemistry); Chemotherapeutic agents; Antidotes. (KT).

The program is directed at the design and synthesis of new compounds for use in the management of organophosphorus poisoning. In the past year 24 compounds were submitted: 12 organophosphinates, one organophosphinic acid, one organophosphinothioate, one organophosphonate, 3 organophosphates, 2 ferrocene carbamates, one each 2-aminoethylseleninic and selenonic acids, phenyl valerate and 2,2-dimethyl-3-hydroxybutylamine. The purpose of the contract is to maintain and operate a synthesis laboratory to provide chemical compounds needed in the development programs of the U.S. Army Medical Research Institute of Chemical Defense (ICD) Edgewood Area, Aberdeen Proving Ground, Maryland.