Rheumatic syndromes caused by antirheumatic drugs.
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Anti-Inflammatory Agents↗
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Second-line drugs used in recent-onset rheumatoid arthritis in Brittany (France).
OBJECTIVE: The management of recent-onset rheumatoid arthritis (RA) is not well standardized. We conducted a survey of drugs prescribed to RA patients in Brittany at presentation and during the first 1 to 3 years of follow-up. METHODS: A cohort of 270 patients with recent-onset inflammatory joint disease was recruited between 1995 and 1997. The evaluation at presentation included a medical history, a thorough physical examination, and a standard battery of investigations. Follow-up at 6-month intervals was offered. At the last visit, between June and December 1999, a panel of five rheumatologists established that 98 patients had RA. RESULTS: At presentation, hydroxychloroquine and injectable gold were the most widely used second-line drugs, and only two patients were offered a combination of second-line drugs. At the last visit, the most commonly used drugs were methotrexate, injectable gold, and hydroxychloroquine (23, 23, and 21 patients, respectively); only three patients were on more than one second-line drug and 38 (38/98, 39%) patients were on glucocorticoid therapy. CONCLUSION: Rheumatologists in Brittany prefer monotherapy with hydroxychloroquine or injectable gold as the initial treatment. Later, they rely mainly on methotrexate, injectable gold, and hydroxychloroquine, often in combination with glucocorticoid therapy.
Antirheumatic Agents↗
Use of disease-modifying antirheumatic drugs in patients with psoriatic arthritis.
UNLABELLED: Few prospective placebo-controlled studies have evaluated disease-modifying antirheumatic drugs (DMARDs) in the treatment of peripheral psoriatic arthritis. OBJECTIVE: To evaluate second-line treatments used in clinical practice in patients with psoriatic arthritis. METHOD: We studied a cross-section of 100 consecutive patients seen by hospital-based or office-based rheumatologists for psoriatic arthritis. PATIENTS: The 55 men and 45 women had a mean age of 48 years (range, 17-79 years) and a mean disease duration of 7 years (range, 1-24 years). RESULTS: The most commonly used DMARDs were sulfasalazine, gold, methotrexate, and hydroxychloroquine (64, 43, 41 et 17 patients, respectively). These drugs had been stopped because of inefficacy in 31%, 31%, 12%, and 53% of patients, respectively, and because of adverse events in 23%, 44%, 22%, and 41% of patients, respectively. At the time of the study, mean treatment durations were 15, 21, 34, and 12 months, respectively, and the drugs were still being used in 45%, 21%, 66%, and 6% of patients. CONCLUSION: Our data confirm the value of methotrexate and salazopyrine. Methotrexate had the best risk/benefit ratio. Gold was often responsible for side effects. Hydroxychloroquine was inadequately effective and poorly tolerated.
Adolescent↗
[Gold salt-induced lung disease].
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Antirheumatic Agents↗
Synthesis and ribosome binding properties of model mRNAs modified with undecagold cluster.
The synthesis and purification of short model messenger RNAs modified with undecagold cluster are described. A monoamino undecagold cluster was introduced on the oxidized 3' cis-glycol group of the mRNA followed by reduction of the formed Schiff's base. The stability of the modified mRNA under the conditions used for in vitro messenger RNA translation is studied. The possibility of the formation of a specific translational initiation complex with bacterial ribosomes and modified mRNAs is shown. The results of these experiments indicate that the attachment of an undecagold cluster to a mRNA is a useful tool for electron microscopic and crystallographic studies.
Base Sequence↗
Synthesis of an acetylcholine receptor-specific toxin derivative regioselectively labeled with an undecagold cluster.
The regioselective modification of a snake curaremimetic toxin is described. Toxin-alpha from Naja nigricollis was derivatized with an electron-dense maleimido undecagold cluster 5. The cluster-bound obtained toxin 8 has a very high affinity for the cholinergic binding site (Ki = 70 pM) of Torpedo marmorata nicotinic receptor. It is harboring a compact heavy atom core of about 8 A which makes it very useful for electron microscopy experiments.
Animals↗
Mapping the lipoyl groups of the pyruvate dehydrogenase complex by use of gold cluster labels and scanning transmission electron microscopy.
This paper describes the organization of lipoyl moieties within the pyruvate dehydrogenase (PDH) complex from Escherichia coli as studied in the scanning transmission electron microscope (STEM). The PDH complex is a multienzyme complex consisting of E1, pyruvate dehydrogenase, E2, dihydrolipoyl transacetylase, and E3, dihydrolipoyl dehydrogenase. The core of the complex is the cubic 24-subunit E2 component, which contains the lipoyl moieties bonded to lipoyl-bearing domains. E1 and E3 are associated along the edges (E1) and on the faces (E3) of the core. The lipoyl moieties were reduced with NADH and alkylated with a p-maleimidobenzoyl undecagold cluster complex. The gold labels were found to be bound very nearly specifically by dihydrolipoyl transacetylase (E2). Undecagold clusters were imaged directly by the STEM and also digitally mapped by radial mass analysis. The mass of the E2E3 subcomplex is about half that of the PDH complex. The PDH complex and GC-PDH are both about 420 A in diameter, as determined by radial mass analysis, and the E2E3 subcomplex and GC-E2E3 are 320 and 350 A, respectively. The outer boundary of the E2E3 subcomplex was clearly shown in STEM micrographs by the undecagold labels in GC-E2E3. Data obtained from radial mass analysis of GC-E2E3 and the unlabeled E2E3 subcomplex also showed that the size of the subcomplex is extended by the lipoyl-bearing domains surrounding the central E2 core. The capabilities of lipoyl moieties to undergo translocation over long distances through structural mobility in the lipoyl-bearing domains was confirmed by the observation that many of the lipoyl groups in E2E3 subcomplexes relax outward into space vacated by the removal of E1 during the preparation of the subcomplex from PDH complex. Radial mass analysis of the PDH complex and GC-PDH indicates that lipoyl groups are distributed over a large region of the PDH complex, extending from the central core to 170-180 A from the center of the complex, with the highest density at about 75 A from the particle centers, near the interface between E2 and the associated components E1 and E3.
Escherichia coli↗
Synthesis of undecagold cluster molecules as biochemical labeling reagents. 1. Monoacyl and mono[N-(succinimidooxy)succinyl] undecagold clusters.
This paper describes the synthesis and characterization of succinyl, phthalyl, and N-(succinimidooxy)-succinyl derivatives of the undecagold cluster complex tricyanoheptakis[4,4',4"-phosphinidynetris(benzenemethana mine)]undecagold, 1, molecular formula Au11(CN)3[P(C6-H4CH2NH2)3]7. These are useful as electron-dense reagents for labeling biological structures in preparation for electron microscopic analysis. Limited reaction of 1 with succinic or phthalic anhydrides produces a mixture of mono-, bis-, etc. (N-succinyl)-1 or (N-phthalyl)-1, which can be separated by anion-exchange chromatography at pH 11.5. Yields of monoacylated derivatives can be maximized by controlling the ratio of succinic or phthalic anhydride to 1. The remaining 20 primary amino groups can be dialkylated or acetylated, blocking their participation in further chemical modifications of the carboxylic functional group introduced in the succinylation or phthalylation of 1. These carboxyl groups can be activated as N-hydroxysuccinimido esters, which are acylating derivatives of 1. An example is mono[N-(succinimidooxy)-succinyl]icosa(N,N-dimethyl)-1 whose synthesis is described. Bis- and tris(N-succinyl) and -(N-phthalyl) derivatives of 1 are also produced and isolated in usable quantities.
Chemical Phenomena↗
Synthesis of undecagold cluster molecules as biochemical labeling reagents. 2. Bromoacetyl and maleimido undecagold clusters.
Derivatives of heptakis[4,4',4"-phosphinidynetris(benzenemethanamine) ]undecagold, 1, molecular formula Au11(CN)3[P(C6H4CH2NH3)]7, are described. These include undecagold complexes with a single free primary amino group, a single bromoacetyl group, and a single maleimido group per molecule. Hydrolysis of mono(N-phthalyl)icosa(N-acetyl)-1 at pH 3.2 and 46 degrees C under anaerobic conditions and in the presence of NaBH3CN produces icosa(N-acetyl)-1. Partial acylation of 1 with 1.3 equiv of 2,3-dimethylmaleic anhydride followed by complete acetylation with acetic anhydride produces a mixture consisting largely of mono- and bis(dimethylmaleyl)peracetyl-1. Hydrolysis of 2,3-dimethylmaleimides at pH 3.2 for 1 at 25 degrees C produces a mixture of icosa(N-acetyl)-1, with a single free amino group, and nondea(N-acetyl)-1. This mixture can be quantitatively separated by cation-exchange chromatography at pH 7, giving homogeneous icosa(N-acetyl)-1 in an overall yield of 55%. Icosa(N-acetyl)-1 serves as the starting material for the synthesis of the alkylating derivatives mono(N-bromoacetyl)icosa(N-acetyl)-1 and mono[N-(p-maleimidobenzoyl)]icosa(N-acetyl)-1. These derivatives can be used for alkylating proteins in preparation for electron microscopy.
Acetates↗
Synthesis of undecagold cluster molecules as biochemical labeling reagents. 3. Dimeric cluster with a single reactive amino group.
The synthesis and characterization of a dimeric derivative of the undecagold cluster complex Au11(CN)3[P-(C6H4CH2NH2)3]7, 1, are described. The dimer, 2, consists of cross-linked molecules of 1 in which 41 of the 42 amino groups are acylated, leaving a single free amino group per dimer. This amino group is reactive and can be used to prepare derivatives of 2 for use in labeling biological macromolecules in preparation for electron microscopic analysis. Limited acylation of 1 by 1.3 equiv of citraconic anhydride in aqueous solution, followed by extensive acylation with acetic anhydride at pH 7-7.5, leads to a mixture of monomeric and dimeric products. Hydrolytic removal of N-citraconyl groups at pH 3.2 unmasks a few amino groups. Cation-exchange chromatography at pH 7 separates the products into three main groups, species containing one, two, or three free amino groups, in overall yields of 33%, 28%, and 15%, respectively. The monoamino species consist mainly of 2 and a monomeric product, which are separated by gel exclusion chromatography. 2 migrates as a dimer upon polyacrylamide gel electrophoresis in sodium dodecyl sulfate, and it contains a single free amino group, detectable by its ion-exchange behavior as a monocation at pH 7 and by its reactivity with [14C]phthalic anhydride.
Chemical Phenomena↗
Synthesis, structures, and electrochemistry of gold(III) ethylenediamine complexes and interactions with guanosine 5'-monophosphate.
[Au(en)Cl(2)]Cl.2H(2)O, where en = ethylenediamine (1,2-diaminoethane), has been synthesized, and its structure has been solved for the first time by the single-crystal X-ray diffraction method. The complex has square-planar geometry about Au(III), and the anionic Cl- is located in the apical position and at a distance of 3.3033(10) A compared to 2.2811(9) and 2.2836(11) A for the coordinated Cl-. [Au(en)Cl2]Cl.2H2O belongs to the space group Pbca with a = 11.5610(15) A, b = 12.6399(17) A, c = 13.2156(17) A, alpha = beta = gamma = 90 degrees , and Z = 8. Bond lengths of Au-N are 2.03 A. [Au(en)Cl2]Cl.2H2O is less thermally stable than [Au(en)2]Cl3 because of the replacement of two Cl ligands by a second en ligand in the latter. Cyclic voltammetry shows that the formal potential of Au(III)/Au(0) becomes more negative in the series [AuCl4]-, [Au(en)Cl2]+, and [Au(en)2]3+. 1H, 13C, and 31P NMR reveal that in an aqueous solution [Au(en)Cl2]+ bonds to guanosine 5'-monophosphate, 5'-GMP (1:1 mole ratio), via N7, although the stability is not very high. NMR data also indicate that N7-O6 or N7-phosphate 5'-GMP chelation, as found in some gold(III) nucleotide complexes, is not present. The gold(III) complex undergoes hydrolysis at pH >2.5-3.0 and, therefore, N1 coordination to 5'-GMP is not observed. No direct coordination between 5'-GMP and [Au(en)2]Cl3 is observed.
Electrochemistry↗
Cytotoxicity and antitumor activity of some tetrahedral bis(diphosphino)gold(I) chelates.
We report the cytotoxicity toward B16 cells and antitumor activity in three transplantable tumor models of a series of ionic, tetrahedral, bischelated gold diphosphine complexes of the type [Au1(R2PYPR2')2]X, where Y = (CH2)2, (CH2)3, or cis-CH = CH. The anion (X = Cl, Br, I, CH3SO3, NO3, PF6) had little effect upon activity. The R = R' = phenyl complexes 1, 7, and 8 [Y = (CH2)2, (CH2)3, cis-CH = CH, X = Cl] were the most active against P388 leukemia, with an increase in lifespan ranging from 83 to 92% and were also active against M5076 sarcoma and B16 melanoma. Complexes with pyridyl or fluorophenyl substituents had reduced activities. For the latter, 19F and 31P NMR were used to verify the formation of bischelated gold(I) complexes in solution. The reduced activity of the complex with R = Et and R' = Ph and inactivity with R = R' = Et are discussed in terms of their increased reactivity as reducing agents. 31P NMR studies show that [AuI(Et2P(CH2)2PPh2)2]Cl readily reacts with serum, albumin, and Cu2+ ions to give oxidized ligand.
Animals↗
Inhibition of lysosomal cysteine proteases by a series of Au(I) complexes: a detailed mechanistic investigation.
Complexes of gold(I) have long been used to treat rheumatoid arthritis although the precise biological targets of gold are not well understood. One intriguing therapeutic target of Au(I) is the cathepsin family of lysosomal cysteine proteases. Here, we present the inhibition of cathepsin B by a known Au(I)-based drug and a series of derivatives. The complexes investigated were reversible, competitive inhibitors with IC50 values ranging from 0.3 to 250 microM, depending on the substituents around the Au(I).
Auranofin↗
Toward a novel metal-based chemotherapy against tropical diseases. 3. Synthesis and antimalarial activity in vitro and in vivo of the new gold-chloroquine complex [Au(PPh3)(CQ)]PF6.
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Animals↗
Triplet photophysics of gold(III) porphyrins.
Gold porphyrins are often used as electron-accepting chromophores in donor-acceptor complexes for the study of photoinduced electron transfer, and they can also be involved in triplet-triplet energy-transfer interactions with other chromophores. Since the lowest excited singlet state is very short-lived (240 fs), the triplet state is usually the starting point for the transfer reactions, and it is therefore crucial to understand its photophysics. The triplet state of various gold porphyrins has been reported to have a lifetime of around 1.5 ns at room temperature and to have a biexponential decay both in emission and in transient absorption with decay times of around 10 and 100 micros at 80 K. In this paper, the triplet photophysics of two gold porphyrins (Au(III) 5,15-bis(3,5-di-tert-butylphenyl)-2,8,12,18-tetraethyl-3,7,13,17-tetramethylporphyrin and Au(III) 5,10,15,20-tetra(3,5-di-tert-butylphenyl)porphyrin) are studied by steady-state and time-resolved absorption and emission spectroscopy over a wide temperature range (4-300 K). The study reveals the existence of a dark state with an approximate lifetime of 50 ns, which was not previously observed. This state acts as an intermediate between the short-lived singlet and the triplet state manifold. In addition, we present DFT calculations, in which the core electrons of the central metal were replaced by a pseudopotential to account for the relativistic effects, which suggest that the lowest excited singlet state is an optically forbidden ligand-to-metal charge-transfer (LMCT) state. This LMCT state is an obvious candidate for the experimentally observed dark state, and it is shown to dictate the photophysical properties of gold porphyrins by acting as a gate for triplet state formation versus direct return to the ground state.
Light↗
Prolonged cholestasis and ductopenia following gold salt therapy.
Hepatotoxicity, predominantly cholestatic, is a rare adverse effect of gold salt therapy, which usually completely resolves within a few months. We report the case of a female patient treated for rheumatoid arthritis, who had gold salt overdose, and in whom acute cholestatic hepatitis occurred three weeks after beginning of therapy. Evolution of gold concentration was followed in plasma and urine, as well as in cutaneous and liver dry tissue. Liver biopsy showed marked inflammatory changes of interlobular bile ducts that evolved towards ductopenia, which was responsible for prolonged cholestasis still present 15 months later. In addition, sialadenitis with sicca syndrome was noted six months after onset of the disease. The mechanism of hepatotoxicity was probably immunoallergic since liver lesions were associated with hypersensitivity syndrome including dermatitis and blood and tissue eosinophilia. This is the first report of gold salt hepatotoxicity with histological demonstration of cholangitis followed by ductopenia.
Antirheumatic Agents↗
Deposition of gold in ocular structures, although known, is rare. A case of ocular chrysiasis in a patient of rheumatoid arthritis on gold treatment is presented.
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Antirheumatic Agents↗
ESR observation of the formation of an Au(II) complex in zeolite Y.
Herein we communicate the first time observation of an Au(II) complex stabilized in a zeolite Y supercage, as evidenced by electron spin resonance (ESR); confinement in the zeolite pores obviously stabilizes this unusual oxidation state and prevents it from undergoing disproportionation.
Electron Spin Resonance Spectroscopy↗