LETTERS
weeks in the terminal portion of one such curve. A halflife for gold much greater than 5 days would be consistent with the commonly used monthly gold dosing regimen. If the half-life of gold were only 5 days, then no drug accumulation would occur or be maintained from doses given every 6 half-lives. There are several possible explanations for the variability in reported half-life determinations. Patients who have never received gold therapy may initially handle the drug differently from those maintained on chronic therapy due to potential differences in tissue uptake. Gold is highly bound to albumin, and differences in concentrations of free drug may cause differences in the tissue distribution and excretion of gold. Inadequate experimental design may not allow for detection of a deep compartment for the drug. One of the pharmacokinetic studies (1) after single dose administration was carried out for only 10 days. This is too short a time to kinetically evaluate a drug with an apparent half-life of 5 days or longer. In an attempt to clarify some of these disagreements in the literature, we studied the disposition of gold sodium thiomalate given to 2 healthy male volunteers. Gold sodium thiomalate (Myochrysine), 10 mg, was administered intramuscularly and plasma concentrations were determined as a function of time for 30 days. The plasma samples were assayed for gold content by neutron activation analysis. In both subjects, the drug was rapidly absorbed from the site of injection, with peak concentrations being observed at the first sampling time (30 minutes after dosing). The plasma concentration-time data were best fit by a triexponential equation by using the digital computer program, NONLIN. The apparent half-lives obtained from the terminal log-linear phases of the plasma concentration-time curves are 9.7 and 10.4 days. From visual inspection of the curves, we observe that the terminal log-linear phase does not begin until approximately 14 days after the administration of the drug. These results add validity to the hypothesis that the half-life of gold must be longer than the previously reported values. Such a finding would be consistent with accumulation from monthly maintenance dosing. The determination of an approximate 10 day half-life for gold with the start of the disposition phase occurring 2 weeks after a single dose dictates that an appropriate experimental design for defining gold pharmacokinetics would require sampling over an extended period of time. We are presently undertaking studies that will further define the half-life of gold in patients on chry-
1419
sotherapy. Additionally, we will soon present a more detailed description of the pharmacokinetics of gold in normal volunteers following single intramuscular and intravenous doses. ELAINES. WALLER,PHARMD BS JOSEPHW. MASSARELLA, JAMESE. CROUT,MD GERALDJ. YAKATAN, PhD Drug Dynamics Institute College of Pharmacy The University of Texas at Austin Austin, Texas 78712
REFERENCES 1. Gerber RC, Paulus HE, Bluestone R, Lederer M: Kinetics
of aurothiomalate in serum and synovial fluid. Arthritis Rheum 15:625-629, 1972 2. Gerber RC, Paulus HE, Jennrich RI, Lederer M, Bluestone R, Blahd WH, Pearson CM: Gold kinetics following aurothiomalate therapy: use of a whole-body radiation counter. J Clin Lab Med 83:778-789,1974 3. Gottlieb NL, Smith PM, Smith EM: Pharmacodynamicsof I9’Au and I9’Au labeled aurothiomalate in blood: correlation with course of rheumatoid arthritis, gold toxicity and gold excretion. Arthritis Rheum 17:171-183, 1974 4. Palmer DG, Dunckley JV: Gold levels in serum during the treatment of rheumatoid arthritis with gold sodium thiomalate. Austr NZ J Med 3:461-466, 1973
Effect of hemiparesis on rheumatoid arthritis To the Editor: Nerve lesions and hemiplegia are reported to affect the symmetry of the subsequent development of rheumatic disorders; the paralyzed extremity is spared involvement by rheumatoid arthritis (1-4), tophaceous gout (9,and osteoarthritis (6). This is a report of the effect of hemiparesis occurring in the presence of rheumatoid arthritis of long duration. A 66-year-old, right-handed white man with rheumatoid arthritis for 38 years and chronic symmetrical synovitis developed hemiplegia on the right side following a cardiovascular accident. Latex flocculation was positive 1 :640. X-rays showed symmetrical joint space narrowing, erosions, and subchondral cysts. One month after the stroke there was reduction of the synovial thickening of the right wrist and extensor hood, metacarpophalangeal joints of the right hand, right knee, and ankle. The circumference of the right wrist was 17.9
LETTERS
1420
cm and the left wrist was 19.0 cm. Four months after the stroke there was further reduction in synovial thickening of the right wrist, hand, and knee. At that time the circumference of the right wrist was 17.0 cm and the left 19.0 cm. Joint scan showed less uptake in the right elbow, wrist, hand, knee, and ankle than on the left. Synovial thickening of the joints of the left arm and leg remained unchanged. Sparing of the joints of a paralyzed extremity by rheumatoid arthritis occurring after paralysis has been considered due to either the reduction of movement of the paralyzed limb or to a protective effect of the neural lesion (7,8). Immobilization of joints by casting or splinting relieves pain in a few days, and a reduction in synovitis occurs that may be sustained long after the joint is mobilized (9-1 1). It would be expected that impaired activity after a stroke would reduce the synovitis of the joints of the paralyzed extremity. However, it has been stated that paralysis does not affect the joints if rheumatoid arthritis is already present (1,2). Only one case has been reported where rheumatoid arthritis preceded stroke, and the joints of the paralyzed side were reported to be more painful and swollen 10 months after the stroke and did not respond to corticosteroid drugs (12). The reduction of synovitis in the joints of the paralyzed extremities following stroke, as reported here, lends additional support to the thesis that articular rest has a beneficial effect on the inflammatory lesion of rheumatoid arthritis (13). It is possible that the neural lesion alone affects inflammation as previously suggested, but improvement occumng a few weeks after paralysis suggests that reduced activity, or articular rest, is the principal or singular cause of the change. RICHARDDEANSMITH,MD Arthritis Section John Muir Memorial Hospital Walnut Creek, CA 94598
REFERENCES Thompson M, Bywaters EGL: Unilateral rheumatoid arthritis following hemiplegia. Ann Rheum Dis 21:370-377, 1962 Bland JH, Eddy WM: Hemiplegia and rheumatoid hemiarthritis. Arthritis Rheum 11:72-78, 1968 Kamermann JS: Protective ,effect of traumatic lesions on rheumatoid arthritis. Ann Rheum Dis 25:361-363, 1966 Glick EN: Asymmetrical rheumatoid arthritis after poliomyelitis. Br Med J 3:26-28, 1967
5. Glynn JJ, Clayton ML: Sparing effect of hemiplegia on tophaceous gout. Ann Rheum Dis 35:534-535, 1976 6. Coste F, Forestier J: Hemipkgie et nodosites d’Heberden Contralaterales. Bull SOC Med Hosp Paris 5 1:772-776, 1935 (cited by Glynn and Clayton) 7. Bywaters EGL: Hemiplegia and rheumatoid hemiarthritis. Arthritis Rheum I1:78-79, 1968 8. Rodnan GP: Hemiplegia and rheumatoid hemiarthritis. Arthritis Rheum 11:79, 1968 9. Harris R, Copp EP: Immobilization of the knee joint in rheumatoid arthritis. Ann Rheum Dis 21:353-359, 1962 LO. Partridge REH, Duthie JJR: Controlled trial of the effects of complete immobilization of the joint in rheumatoid arthritis. Ann Rheum Dis 22:91-99, 1963 11. Gault SJ, Spyker JM: Beneficial effect of immobilization of joints in rheumatoid and related arthritides: a splint study using sequential analysis. Arthritis Rheum 12:34 44, 1969 12. Nava P: Conferencias de pratica reumatologica. Brasilmed 67:318-321, 1953 13. Smith RD, Polley HF: Rest therapy for rheumatoid arthritis. Mayo Clin Proc 53:141-145, 1978
Psoriatic arthritis: Results of light and electron microscopy after early and late synovectomy To the Editor: Examination of synovial tissues from 11 patients with psoriatic arthritis revealed several morphologic pictures. Besides the previously well described zones of fibrosis and degeneration of superficial cells, the following were shown: 1) vascular alterations, 2) transitional forms among endotheliocytes, perivascular cells, and fibroblasts as well as 3) lymphoid follicle-like accumulations of round cells. These changes could indicate the presence of an exogenous agent with perhaps strong antigenic effect but in low concentration. Such findings could be interpreted as indicating that in psoriasis there is an immunologic process in stratum synoviale which leads through abnormal cell proliferation and fibrosis to the final destructive event. Data describing the pathologic event will be published in detail elsewhere.
K. M. ROHE M. BIERTHER D. WESSINGHAGE Ernst-Rodenwaldt-lnstitut Koblenz and Rheuma-Klinik West Germany
weeks in the terminal portion of one such curve. A halflife for gold much greater than 5 days would be consistent with the commonly used monthly gold dosing regimen. If the half-life of gold were only 5 days, then no drug accumulation would occur or be maintained from doses given every 6 half-lives. There are several possible explanations for the variability in reported half-life determinations. Patients who have never received gold therapy may initially handle the drug differently from those maintained on chronic therapy due to potential differences in tissue uptake. Gold is highly bound to albumin, and differences in concentrations of free drug may cause differences in the tissue distribution and excretion of gold. Inadequate experimental design may not allow for detection of a deep compartment for the drug. One of the pharmacokinetic studies (1) after single dose administration was carried out for only 10 days. This is too short a time to kinetically evaluate a drug with an apparent half-life of 5 days or longer. In an attempt to clarify some of these disagreements in the literature, we studied the disposition of gold sodium thiomalate given to 2 healthy male volunteers. Gold sodium thiomalate (Myochrysine), 10 mg, was administered intramuscularly and plasma concentrations were determined as a function of time for 30 days. The plasma samples were assayed for gold content by neutron activation analysis. In both subjects, the drug was rapidly absorbed from the site of injection, with peak concentrations being observed at the first sampling time (30 minutes after dosing). The plasma concentration-time data were best fit by a triexponential equation by using the digital computer program, NONLIN. The apparent half-lives obtained from the terminal log-linear phases of the plasma concentration-time curves are 9.7 and 10.4 days. From visual inspection of the curves, we observe that the terminal log-linear phase does not begin until approximately 14 days after the administration of the drug. These results add validity to the hypothesis that the half-life of gold must be longer than the previously reported values. Such a finding would be consistent with accumulation from monthly maintenance dosing. The determination of an approximate 10 day half-life for gold with the start of the disposition phase occurring 2 weeks after a single dose dictates that an appropriate experimental design for defining gold pharmacokinetics would require sampling over an extended period of time. We are presently undertaking studies that will further define the half-life of gold in patients on chry-
1419
sotherapy. Additionally, we will soon present a more detailed description of the pharmacokinetics of gold in normal volunteers following single intramuscular and intravenous doses. ELAINES. WALLER,PHARMD BS JOSEPHW. MASSARELLA, JAMESE. CROUT,MD GERALDJ. YAKATAN, PhD Drug Dynamics Institute College of Pharmacy The University of Texas at Austin Austin, Texas 78712
REFERENCES 1. Gerber RC, Paulus HE, Bluestone R, Lederer M: Kinetics
of aurothiomalate in serum and synovial fluid. Arthritis Rheum 15:625-629, 1972 2. Gerber RC, Paulus HE, Jennrich RI, Lederer M, Bluestone R, Blahd WH, Pearson CM: Gold kinetics following aurothiomalate therapy: use of a whole-body radiation counter. J Clin Lab Med 83:778-789,1974 3. Gottlieb NL, Smith PM, Smith EM: Pharmacodynamicsof I9’Au and I9’Au labeled aurothiomalate in blood: correlation with course of rheumatoid arthritis, gold toxicity and gold excretion. Arthritis Rheum 17:171-183, 1974 4. Palmer DG, Dunckley JV: Gold levels in serum during the treatment of rheumatoid arthritis with gold sodium thiomalate. Austr NZ J Med 3:461-466, 1973
Effect of hemiparesis on rheumatoid arthritis To the Editor: Nerve lesions and hemiplegia are reported to affect the symmetry of the subsequent development of rheumatic disorders; the paralyzed extremity is spared involvement by rheumatoid arthritis (1-4), tophaceous gout (9,and osteoarthritis (6). This is a report of the effect of hemiparesis occurring in the presence of rheumatoid arthritis of long duration. A 66-year-old, right-handed white man with rheumatoid arthritis for 38 years and chronic symmetrical synovitis developed hemiplegia on the right side following a cardiovascular accident. Latex flocculation was positive 1 :640. X-rays showed symmetrical joint space narrowing, erosions, and subchondral cysts. One month after the stroke there was reduction of the synovial thickening of the right wrist and extensor hood, metacarpophalangeal joints of the right hand, right knee, and ankle. The circumference of the right wrist was 17.9
LETTERS
1420
cm and the left wrist was 19.0 cm. Four months after the stroke there was further reduction in synovial thickening of the right wrist, hand, and knee. At that time the circumference of the right wrist was 17.0 cm and the left 19.0 cm. Joint scan showed less uptake in the right elbow, wrist, hand, knee, and ankle than on the left. Synovial thickening of the joints of the left arm and leg remained unchanged. Sparing of the joints of a paralyzed extremity by rheumatoid arthritis occurring after paralysis has been considered due to either the reduction of movement of the paralyzed limb or to a protective effect of the neural lesion (7,8). Immobilization of joints by casting or splinting relieves pain in a few days, and a reduction in synovitis occurs that may be sustained long after the joint is mobilized (9-1 1). It would be expected that impaired activity after a stroke would reduce the synovitis of the joints of the paralyzed extremity. However, it has been stated that paralysis does not affect the joints if rheumatoid arthritis is already present (1,2). Only one case has been reported where rheumatoid arthritis preceded stroke, and the joints of the paralyzed side were reported to be more painful and swollen 10 months after the stroke and did not respond to corticosteroid drugs (12). The reduction of synovitis in the joints of the paralyzed extremities following stroke, as reported here, lends additional support to the thesis that articular rest has a beneficial effect on the inflammatory lesion of rheumatoid arthritis (13). It is possible that the neural lesion alone affects inflammation as previously suggested, but improvement occumng a few weeks after paralysis suggests that reduced activity, or articular rest, is the principal or singular cause of the change. RICHARDDEANSMITH,MD Arthritis Section John Muir Memorial Hospital Walnut Creek, CA 94598
REFERENCES Thompson M, Bywaters EGL: Unilateral rheumatoid arthritis following hemiplegia. Ann Rheum Dis 21:370-377, 1962 Bland JH, Eddy WM: Hemiplegia and rheumatoid hemiarthritis. Arthritis Rheum 11:72-78, 1968 Kamermann JS: Protective ,effect of traumatic lesions on rheumatoid arthritis. Ann Rheum Dis 25:361-363, 1966 Glick EN: Asymmetrical rheumatoid arthritis after poliomyelitis. Br Med J 3:26-28, 1967
5. Glynn JJ, Clayton ML: Sparing effect of hemiplegia on tophaceous gout. Ann Rheum Dis 35:534-535, 1976 6. Coste F, Forestier J: Hemipkgie et nodosites d’Heberden Contralaterales. Bull SOC Med Hosp Paris 5 1:772-776, 1935 (cited by Glynn and Clayton) 7. Bywaters EGL: Hemiplegia and rheumatoid hemiarthritis. Arthritis Rheum I1:78-79, 1968 8. Rodnan GP: Hemiplegia and rheumatoid hemiarthritis. Arthritis Rheum 11:79, 1968 9. Harris R, Copp EP: Immobilization of the knee joint in rheumatoid arthritis. Ann Rheum Dis 21:353-359, 1962 LO. Partridge REH, Duthie JJR: Controlled trial of the effects of complete immobilization of the joint in rheumatoid arthritis. Ann Rheum Dis 22:91-99, 1963 11. Gault SJ, Spyker JM: Beneficial effect of immobilization of joints in rheumatoid and related arthritides: a splint study using sequential analysis. Arthritis Rheum 12:34 44, 1969 12. Nava P: Conferencias de pratica reumatologica. Brasilmed 67:318-321, 1953 13. Smith RD, Polley HF: Rest therapy for rheumatoid arthritis. Mayo Clin Proc 53:141-145, 1978
Psoriatic arthritis: Results of light and electron microscopy after early and late synovectomy To the Editor: Examination of synovial tissues from 11 patients with psoriatic arthritis revealed several morphologic pictures. Besides the previously well described zones of fibrosis and degeneration of superficial cells, the following were shown: 1) vascular alterations, 2) transitional forms among endotheliocytes, perivascular cells, and fibroblasts as well as 3) lymphoid follicle-like accumulations of round cells. These changes could indicate the presence of an exogenous agent with perhaps strong antigenic effect but in low concentration. Such findings could be interpreted as indicating that in psoriasis there is an immunologic process in stratum synoviale which leads through abnormal cell proliferation and fibrosis to the final destructive event. Data describing the pathologic event will be published in detail elsewhere.
K. M. ROHE M. BIERTHER D. WESSINGHAGE Ernst-Rodenwaldt-lnstitut Koblenz and Rheuma-Klinik West Germany
