The sensitivity and specificity of pain diagrams in rheumatic disease referrals.

OBJECTIVES: To determine patterns on pain diagrams and corresponding diagnoses in patients referred to a rheumatology clinic and their sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively). METHODS: All new adult patient referrals from two rheumatologists over 6 years were reviewed and eligible if a pain diagram had been completed and they were not previously diagnosed with a rheumatic disease. Pain diagrams completed by the patient were organized into patterns based on the location of joint and/or soft tissue areas by two independent observers. RESULTS: A total of 1101 patients were included. Five major patterns evolved: soft tissue (widespread pain or regional pain such as an entire arm) (n = 236), symmetrical articular (n = 647), asymmetrical articular (n = 136), monoarticular (n = 35) and back (n = 46); 480 had inflammatory arthritis, of whom 121 had RA, 35 PsA, 46 SpAs and 63 crystal arthropathy. FM or chronic pain also occurred in 63 and 25 had PMR. The sensitivity, specificity, PPV and NPV for polyarticular symmetrical pattern in RA was 87.6, 44.7, 16.4 and 96.7% and for inflammatory arthritis with symmetrical or asymmetrical pattern was 82.3, 37.4, 50.4 and 73.2%; and a back pattern in AS was 10.9, 98.9, 41.7 and 96.2%. Inter-rater reliability was high for monoarticular, symmetrical and asymmetrical patterns (intra-class correlation coefficient ≥ 0.777). CONCLUSION: Pain diagram patterns may help to increase the likelihood of various rheumatic diagnoses including polyarticular pattern and inflammatory arthritis, and there was high inter-rater reliability. However, testing the value of pain diagrams in addition to a referral note is necessary to determine if they have added value.

Structure-activity relationships for inhibition of human cholinesterases by alkyl amide phenothiazine derivatives.

Several lines of evidence indicate that inhibition of butyrylcholinesterase (BuChE) is important in the treatment of certain dementias. Further testing of this concept requires inhibitors that are both BuChE-selective and robust. N-alkyl derivatives (2, 3, 4) of phenothiazine (1) have previously been found to inhibit only BuChE in a mechanism involving pi-pi interaction between the phenothiazine tricyclic ring system and aromatic residues in the active site gorge. To explore features of phenothiazines that affect the selectivity and potency of BuChE inhibition, a series of N-carbonyl derivatives (5-25) was synthesized and examined for the ability to inhibit cholinesterases. Some of the synthesized derivatives also inhibited AChE through a different mechanism involving carbonyl interaction within the active site gorge. Binding of these derivatives takes place within the gorge, since this inhibition disappears when the molecular volume of the derivative exceeds the estimated active site gorge volume of this enzyme. In contrast, BuChE, with a much larger active site gorge, exhibited inhibition that increased directly with the molecular volumes of the derivatives. This study describes two distinct mechanisms for binding phenothiazine amide derivatives to BuChE and AChE. Molecular volume was found to be an important parameter for BuChE-specific inhibition.

Inhibition of human cholinesterases by drugs used to treat Alzheimer disease.

Current approaches to the treatment of cognitive and behavioral symptoms of Alzheimer disease emphasize the use of cholinesterase inhibitors. The kinetic effects of the cholinesterase inhibitors donepezil, galantamine, metrifonate, physostigmine, rivastigmine, and tetrahydroaminoacridine were examined with respect to their action on the esterase and aryl acylamidase activities of human acetylcholinesterase (AChE) and human butyrylcholinesterase (BuChE). Each of these drugs inhibited both AChE and BuChE, but to different degrees. Inhibition of BuChE by these compounds was approximately the same, or better, when acetylthiocholine, the analog of the neurotransmitter acetylcholine, was used as the substrate, instead of butyrylthiocholine. In addition, for these drugs, the inhibition of aryl acylamidase activity paralleled that observed for inhibition of esterase activity of AChE and BuChE. Given that drugs that are currently in use for the treatment of Alzheimer disease inhibit both AChE and BuChE, the development of drugs targeted toward the exclusive inhibition of one or the other cholinesterase may be important for understanding the relative importance of inhibition of BuChE and AChE in the treatment of this disease.