770
ethanol intake in rats. In the initial study alcoholics relapsed on placebo (25 of 37) than on acamprosate (13 of 33). This result prompted the researchers to undertake a larger study, and the findings have now been reported.22 Of 569 patients recruited from thirty centres in France, 356 (181 acamprosate, 175 placebo) completed three months’ follow-up. This trial illustrates many of the difficulties associated with multicentre studies. The researchers chose as a main outcome the measurement of serum gamma-glutamyl transpeptidase (GGT), as an index of continuing
agents in the belief that every little bit extra helps. On
voluntary
existing evidence, they would be unwise to base their choice of NSAID on any supposed cartilage-sparing effect.
more
Docherty M. "Chondroprotection" by non-steroidal anti-inflammatory drugs. Ann Rheum Dis 1989; 48: 619-21. 2. Huskisson EC. Clinical aspects of chondroprotection. Semin Arthritis Rheum 1990; 19 (suppl 1): 30-32. 3. Radin EL, Burr DB. Hypothesis: joints can heal. Semin Arthritis Rheum 1984; 13: 293-302. 4. Herman JH, Appel AM, Hess EV. Modulation of cartilage destruction by select nonsteroidal antiinflammatory drugs. In vitro effect on the synthesis and activity of catabolism-inducing cytokines produced by osteoarthritic and rheumatoid synovial fluid. Arthritis Rheum 1987; 30: 1.
257-65.
Fujii K, Tajiri K, Kajiwara T, Tanaka T, Moruta K. Effects of NSAID on collagen and proteoglycan synthesis of cultured chondrocytes. J Rheumatol 1989; 18 (suppl): 28-31. 6. Pelletier JP, Martel-Pelletier J. Evidence for the involvement of mterleukin 1 in human osteoarthritic cartilage degradation: protective effect of NSAID. J Rheumatol 1989; 18 (suppl): 19-27. 7. Ghosh P. Anti-rheumatic drugs and cartilage. Clin Rheumatol 1988; 2: 5.
309-38. 8. McKenzie LS,
Horsburgh BA, Ghosh P, Taylor TKF. Effect of anti-inflammatory drugs on sulphated glycosaminoglycan synthesis in aged human articular cartilage. Ann Rheum Dis 1976; 35: 487-97. 9. Burkhardt D, Ghosh P. Laboratory evaluation of antiarthritic drugs as potential chondro-protective agents. Semin Arthritis Rheum 1987; 17 (suppl 1): 3-34. 10. Wolfe AD. Setting the scene and posing the questions. Br J Rheumatol 1988; 27 (suppl 1): 1-4. 11. Scott DL, Greenwood A, Davies J, Maddison PJ, Maddison MC, Hall ND. Radiological progression in rheumatoid arthritis: do Dpenicillamine and hydroxychloroquine have different effects? Br J Rheumatol 1990; 29: 126-27. 12. Pullar T, Capell HA. A rheumatological dilemma: is it possible to modify the course of rheumatoid arthritis? Can we answer the question? Ann Rheum Dis 1985; 44: 134-40. 13. Dawes PT. Radiological assessment of outcome in rheumatoid arthritis. Br J Rheumatol 1988; 27 (suppl 1): 21-36. 14. Acheson RM. Osteoarthrosis—the mystery crippler. J Rheumatol 1983; 10: 174-76. 15. Pattrick M, Aldridge S, Hamilton E, Manhire A, Docherty M. A controlled study of hand function in nodal and erosive osteoarthritis. Ann Rheum Dis 1989; 48: 978-82. 16. Ronningen H, Langeland N. Indomethacin treatment in osteoarthritis of the hip joint. Does the treatment interfere with the natural course of the disease? Acta Orthop Scand 1979; 50: 169-74. 17. Newman NM, Ling RSM. Acetabular bone destruction related to non-steroidal anti-inflammatory drugs. Lancet 1985; ii: 11-14. 18. Rashad S, Revell P, Hemingway A, Low F, Rainsford K, Walker F. Effect of non-steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet 1989; ii: 519-22. 19. Docherty M, Holt M, Macmillan P, Watt I, Dieppe PA. A reappraisal of "analgesic hip". Ann Rheum Dis 1986; 45: 272-76. 20. Orme M. Profile of non-steroidal anti-inflammatory drugs. Prescriber’s J 1990; 30: 95-100.
Acamprosate, citalopram, and alcoholism Drug treatments for alcoholism have generally been directed either
at acute
withdrawal symptoms-
benzodiazepines, p-blockers, and chlorrnethiazoleor at inducing aversion for alcohol. Thus disulfiram, an aldehyde dehydrogenase inhibitor that leads to accumulation of acetaldehyde with secondary flushing and tachycardia if the patient consumes alcohol, has been widely used but with limited success. In 1985 Lhuintre and colleagues described the effects of calcium acetyl homotaurinate, an agonist of gammaaminobutyric acid in man. This compound, which now has the approved name of acamprosate, decreases
alcohol ingestion. However, they did not specify before the study that a standard method should be adopted for analysis of this enzyme, so the upper limit of normal is reported over a three-fold range of concentration depending on the method used by each centre. It is unclear how this upper limit of normal was set. To overcome this difficulty, the French workers normalised results by expressing them as multiples of laboratory upper limits. There does not seem to have been a systematic attempt to measure the frequency of alcohol ingestion in this experiment. Blood alcohol measurements were not obtained in all patients; the researchers say that some investigators "thought it [blood alcohol determination] incompatible with their management of alcoholic patients". The only statistically significant difference at the end of the study was in the multiple of upper limit of normal to which the GGT was raised (acamprosate 1-38; SD 1-56, placebo 2,02, 1’39). In absolute terms, the GGT fell over three months from 191 4 (SD 253-3) to 48.4 (57-9) on acamprosate, and from 206-4 (245-0) to 73.2 (131-1) on placebo. Red cell mean volume fell to a similar degree in both groups (acamprosate 102-3 [5-9] to 95-9 [5-5]; placebo 1021 [6-7] to 96-4 [5-9] at three months). Some general trends suggested an effect of active treatment on other
including therapeutic efficacy as assessed by patient and doctor, but these did not reach statistical significance. Since the initial report with acamprosate Naranjo and colleagues3 have published their work on citalopram, a serotonin uptake inhibitor. Citalopram in a dose of 40 mg per day, but not in a dose of 20 mg, significantly reduced the number of drinks consumed and the number of abstinence days in male nondepressed problem drinkers. This was a much smaller study (19 patients in the 40 mg treatment group) and the hepatic effects of alcohol were not investigated in detail. Nevertheless, the results suggest other possible approaches to alcoholism.
measures,
1. Lhuintre J-P, Daoust M, Moore ND, et al. Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet 1985; i: 1014-16. 2. Lhuintre J-P, Moore ND, Tran G, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcoholism 1990; 25: 613-22. 3. Naranjo CA, Sellers EM, Sullivan JT, Woodley DV, Kadlec K, Sykora K. The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 1987; 41: 266-74.
ethanol intake in rats. In the initial study alcoholics relapsed on placebo (25 of 37) than on acamprosate (13 of 33). This result prompted the researchers to undertake a larger study, and the findings have now been reported.22 Of 569 patients recruited from thirty centres in France, 356 (181 acamprosate, 175 placebo) completed three months’ follow-up. This trial illustrates many of the difficulties associated with multicentre studies. The researchers chose as a main outcome the measurement of serum gamma-glutamyl transpeptidase (GGT), as an index of continuing
agents in the belief that every little bit extra helps. On
voluntary
existing evidence, they would be unwise to base their choice of NSAID on any supposed cartilage-sparing effect.
more
Docherty M. "Chondroprotection" by non-steroidal anti-inflammatory drugs. Ann Rheum Dis 1989; 48: 619-21. 2. Huskisson EC. Clinical aspects of chondroprotection. Semin Arthritis Rheum 1990; 19 (suppl 1): 30-32. 3. Radin EL, Burr DB. Hypothesis: joints can heal. Semin Arthritis Rheum 1984; 13: 293-302. 4. Herman JH, Appel AM, Hess EV. Modulation of cartilage destruction by select nonsteroidal antiinflammatory drugs. In vitro effect on the synthesis and activity of catabolism-inducing cytokines produced by osteoarthritic and rheumatoid synovial fluid. Arthritis Rheum 1987; 30: 1.
257-65.
Fujii K, Tajiri K, Kajiwara T, Tanaka T, Moruta K. Effects of NSAID on collagen and proteoglycan synthesis of cultured chondrocytes. J Rheumatol 1989; 18 (suppl): 28-31. 6. Pelletier JP, Martel-Pelletier J. Evidence for the involvement of mterleukin 1 in human osteoarthritic cartilage degradation: protective effect of NSAID. J Rheumatol 1989; 18 (suppl): 19-27. 7. Ghosh P. Anti-rheumatic drugs and cartilage. Clin Rheumatol 1988; 2: 5.
309-38. 8. McKenzie LS,
Horsburgh BA, Ghosh P, Taylor TKF. Effect of anti-inflammatory drugs on sulphated glycosaminoglycan synthesis in aged human articular cartilage. Ann Rheum Dis 1976; 35: 487-97. 9. Burkhardt D, Ghosh P. Laboratory evaluation of antiarthritic drugs as potential chondro-protective agents. Semin Arthritis Rheum 1987; 17 (suppl 1): 3-34. 10. Wolfe AD. Setting the scene and posing the questions. Br J Rheumatol 1988; 27 (suppl 1): 1-4. 11. Scott DL, Greenwood A, Davies J, Maddison PJ, Maddison MC, Hall ND. Radiological progression in rheumatoid arthritis: do Dpenicillamine and hydroxychloroquine have different effects? Br J Rheumatol 1990; 29: 126-27. 12. Pullar T, Capell HA. A rheumatological dilemma: is it possible to modify the course of rheumatoid arthritis? Can we answer the question? Ann Rheum Dis 1985; 44: 134-40. 13. Dawes PT. Radiological assessment of outcome in rheumatoid arthritis. Br J Rheumatol 1988; 27 (suppl 1): 21-36. 14. Acheson RM. Osteoarthrosis—the mystery crippler. J Rheumatol 1983; 10: 174-76. 15. Pattrick M, Aldridge S, Hamilton E, Manhire A, Docherty M. A controlled study of hand function in nodal and erosive osteoarthritis. Ann Rheum Dis 1989; 48: 978-82. 16. Ronningen H, Langeland N. Indomethacin treatment in osteoarthritis of the hip joint. Does the treatment interfere with the natural course of the disease? Acta Orthop Scand 1979; 50: 169-74. 17. Newman NM, Ling RSM. Acetabular bone destruction related to non-steroidal anti-inflammatory drugs. Lancet 1985; ii: 11-14. 18. Rashad S, Revell P, Hemingway A, Low F, Rainsford K, Walker F. Effect of non-steroidal anti-inflammatory drugs on the course of osteoarthritis. Lancet 1989; ii: 519-22. 19. Docherty M, Holt M, Macmillan P, Watt I, Dieppe PA. A reappraisal of "analgesic hip". Ann Rheum Dis 1986; 45: 272-76. 20. Orme M. Profile of non-steroidal anti-inflammatory drugs. Prescriber’s J 1990; 30: 95-100.
Acamprosate, citalopram, and alcoholism Drug treatments for alcoholism have generally been directed either
at acute
withdrawal symptoms-
benzodiazepines, p-blockers, and chlorrnethiazoleor at inducing aversion for alcohol. Thus disulfiram, an aldehyde dehydrogenase inhibitor that leads to accumulation of acetaldehyde with secondary flushing and tachycardia if the patient consumes alcohol, has been widely used but with limited success. In 1985 Lhuintre and colleagues described the effects of calcium acetyl homotaurinate, an agonist of gammaaminobutyric acid in man. This compound, which now has the approved name of acamprosate, decreases
alcohol ingestion. However, they did not specify before the study that a standard method should be adopted for analysis of this enzyme, so the upper limit of normal is reported over a three-fold range of concentration depending on the method used by each centre. It is unclear how this upper limit of normal was set. To overcome this difficulty, the French workers normalised results by expressing them as multiples of laboratory upper limits. There does not seem to have been a systematic attempt to measure the frequency of alcohol ingestion in this experiment. Blood alcohol measurements were not obtained in all patients; the researchers say that some investigators "thought it [blood alcohol determination] incompatible with their management of alcoholic patients". The only statistically significant difference at the end of the study was in the multiple of upper limit of normal to which the GGT was raised (acamprosate 1-38; SD 1-56, placebo 2,02, 1’39). In absolute terms, the GGT fell over three months from 191 4 (SD 253-3) to 48.4 (57-9) on acamprosate, and from 206-4 (245-0) to 73.2 (131-1) on placebo. Red cell mean volume fell to a similar degree in both groups (acamprosate 102-3 [5-9] to 95-9 [5-5]; placebo 1021 [6-7] to 96-4 [5-9] at three months). Some general trends suggested an effect of active treatment on other
including therapeutic efficacy as assessed by patient and doctor, but these did not reach statistical significance. Since the initial report with acamprosate Naranjo and colleagues3 have published their work on citalopram, a serotonin uptake inhibitor. Citalopram in a dose of 40 mg per day, but not in a dose of 20 mg, significantly reduced the number of drinks consumed and the number of abstinence days in male nondepressed problem drinkers. This was a much smaller study (19 patients in the 40 mg treatment group) and the hepatic effects of alcohol were not investigated in detail. Nevertheless, the results suggest other possible approaches to alcoholism.
measures,
1. Lhuintre J-P, Daoust M, Moore ND, et al. Ability of calcium bis acetyl homotaurine, a GABA agonist, to prevent relapse in weaned alcoholics. Lancet 1985; i: 1014-16. 2. Lhuintre J-P, Moore ND, Tran G, et al. Acamprosate appears to decrease alcohol intake in weaned alcoholics. Alcohol Alcoholism 1990; 25: 613-22. 3. Naranjo CA, Sellers EM, Sullivan JT, Woodley DV, Kadlec K, Sykora K. The serotonin uptake inhibitor citalopram attenuates ethanol intake. Clin Pharmacol Ther 1987; 41: 266-74.
