Letter
evaluation of the metacarpalphalangeal, proximal, distal, and interphalangeal joints of each finger excluding the thumb bilaterally, wrist, elbow, and cervical spine (1,6). Results were recorded as positive or negative for each joint. Quantitative evaluation was accomplished with the use of the standard goniometer ARLAN L. ROSENBLOOM, MD MARIA BUITHIEU, MD for the wrist and metacarpalphalangeal KATHLEEN A. JELLIFFE, BSC joints and for flexion of the interphalanROGER D. AITCHISON, SCM geal joints and recorded in degrees of JOSEPH A. TRUGLIA, MD mobility with the use of the Klein device for determining limitation of extension of the interphalangeal joints (6). Bilateral grip strength of the hand This study was undertaken as a ainless and nondisabling limitation was determined using a dynamometer. A of joint mobility (LJM), primarily double-blind placebo-controlled trial of neurological examination was conducted affecting the hands, has been found the aldose reductase inhibitor, ponalrewith the method of Dyck et al. (7). Posin —50% of postadolescent patients with stat (5), in 13 white patients (11 men, 2 tural changes in blood pressure were de>5 yr duration of diabetes, with age be- women), age 18-25 yr, with diabetes termined after 15 min in the supine poing a more important determinant than duration of 6-23 yr. A 1 mo singlesition. Heart rate and blood pressure duration of diabetes, as is also seen with blinded placebo-treated baseline period response to strain were determined in other complications (1). Several studies was followed by 6 mo of double-blinded the nondominant arm while the patient have indicated an approximately fourfold treatment (ponalrestat n = 7, placebo maintained 30% of maximal grip risk of microvascular complications in n = 6) and a 1 mo single-blinded plastrength in the dominant hand. those with LJM as opposed to those with- cebo washout period. Periodic safety and The protocol was approved by out (1-3). Thus, any intervention that efficacy evaluations included a complete the Institutional Review Board of the would reduce LJM could, theoretically, hematologic profile, chemical profile, University of Florida Health Science improve the long-term prognosis for the urinalysis, and physical examination. Center. There were no study withdrawals more serious complications of insulin- Glucose control was assessed by deteror dropouts. mination of glycosylated hemoglobin dependent diabetes mellitus (IDDM). Individual joint measurements Such a possibility was suggested (GHb) concentrations. LJM was staged were summarized into overall scores for by the report of improvement in LJM 1-4 according to established criteria (1) each patient and changes after 6 mo of and patients were randomly assigned with the use of an aldose reductase intreatment using standard parametric t within each of two groups stratified by hibitor, sorbinil, in three patients who tests. These scores were combined to stage of LJM to receive either ponalrestat had substantial functional impairment form an overall efficacy score for the ef(500 mg once daily) or a matching plabut who did not have the syndrome defect on LJM using the rank-sum method scribed in young patients (4). Nonethe- cebo. Patients were instructed to return of O'Brien (8) and comparisons were unused tablets at the next study visit for less, other connective tissue proliferation made by standard t tests. The individual syndromes seen in diabetes might have a determination of compliance, which was overall score for qualitative joint assessvery high. similar biochemical basis to LJM. Were ment was the total number of joints rated this to be true, the milder changes of All examinations were conducted as limited at each assessment. The quanyoung patients with LJM should respond by the same investigator (M.B.). Qualitatitative measurements of extension and most rapidly and dramatically to an in- tive assessment of joint mobility was carflexion were combined to produce an tervention that interrupts the process. ried out as previously described with appropriate single number indicating the arc of motion for each joint. These arc of motion scores were averaged to form a single quantitative joint assessment score FROM THE DIVISION OF ENDOCRINOLOGY, DEPARTMENT OF PEDIATRICS, UNIVERSITY OF FLORIDA COLLEGE for each patient visit. OF MFDICINF, GAINESVILLE, FLORIDA; AND THE ICI PHARMACEUTICALS GROUP, ICI AMERICAS INC., The averaging approach might WILMINGTON, DELAWARE. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO ARLAN L. ROSENBLOOM, MD, J-296 JHMHC, have masked effects of treatment localGAINESVILLE, FL 32610. ized to the joints most affected by LJM,
Effect of an Aldose Reductase Inhibiting Agent on Limited Joint Mobility in ID DM
P
588
DIABETES CARE, VOLUME 15, NUMBER 4, APRIL 1992
Letter
those of digits four and five. Therefore, separate t tests were done to compare changes in extension (the more common limitation) for these digits. Neurological examinations were scored as the sum of three components, muscle strength (0-4), reflexes (0-3), and sensory loss (0-2). The demographics, diabetes duration, and baseline measures of the ponalrestat-treated and placebo assigned groups were comparable except that the two women were randomized to the placebo group. The five efficacy measures (qualitative and quantitative joint scores, grip strength, summed LJM score, and neurological examination score) showed no apparent drug effect during the 6 mo treatment period. Separate analyses of the joints of the fourth and fifth digits failed to unmask a treatment effect. There was also no significant alteration in the response of diastolic blood pressure to hand grip strain in the ponalrestat-treated group compared with the placebo-treated group. No effect on neurological examination scores was noted. Laboratory studies revealed no significant differences between ponalrestattreated and placebo-treated groups for hemoglobin, erythrocyte counts, lymphocyte counts, platelet counts, cell differential, lipid levels, serum total protein, albumin, electrolytes, calcium, phos-
DIABETES CARE, VOLUME 15,
NUMBER 4, APRIL
phate levels, or liver function studies. There was a significant ponalrestatrelated change in serum uric acid level, a decrease of 86.3 |xmol from baseline (mean 253.7 |xmol). After a 1 mo washout, serum uric acid levels approached the level of the baseline mean (mean 268.5 |jimol). No changes were seen in urinalysis in either group. GHb levels increased a mean ± SD of 0.27 ± 1.58% in the ponalrestattreated patients and decreased a mean ± SD of 0.40 ± 1.02% in the placebotreated patients during the 6 mo treatment period, a treatment effect of — 0.67%, which was insignificant. Our patients failed to demonstrate improvement in joint mobility with a 6 -mo trial of a potent aldose reductase inhibitor.
2.
3.
4.
5.
6. Acknowledgments—This study was supported by a grant from ICI Pharmaceuticals Group and by contracts with the Department of Health and Rehabilitative Services of the State of Florida for the Diabetes Research, Education, and Treatment Center, and the Regional Diabetes Program for Children and Youth.
References 1. Rosenbloom AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M: Limited
1992
7.
8.
joint mobility in childhood diabetes indicates increased risk for microvaseular disease. N EnglJ Med 305:191-94, 1981 Kennedy L, Archer DB, Campbell SL, Beacom R, Carson DJ, Johnston PB, Maguire CJ: Limited joint mobility in type 1 diabetes mellitus. Postgrad Med J 54:481-84, 1982 Starkman HS, Gleason RE, Rand LI, Miller DE, Soeldner JS: Limited joint mobility (LJM) of the hand in patients with diabetes mellitus: relation to chronic complications. Ann Rheum Dis 45:130-35, 1986 Eaton RP, Sibbett WL, Harsh A: The effect of an aldose reductase inhibiting agent on limited joint mobility in diabetic patients. JAMA 253:1437-40, 1985 Stribling D, Perkins CM, Smith JC, Uiudadio C: Diabetic neuropathy and its treatment. Drugs Today 25:221-47, 1989 Buithieu M, Rosenbloom AL, Cordon M, Thomas JL, Klein R: Objective measurement of limited joint mobility (LJM) in diabetes (Abstract). Pediatr Res 23:388, 1988 Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O'Brien PC, Grina LA, Palumbo PJ, Swanson CJ: Human diabetic endoneurial sorbitol, fructose and myo-inositol related to sural nerve morphometry. Ann Neurol 8:590-96, 1980 O'Brien PC: Procedures for comparing samples with multiple endpoints. Biometrics 1079-87, 1984
589
evaluation of the metacarpalphalangeal, proximal, distal, and interphalangeal joints of each finger excluding the thumb bilaterally, wrist, elbow, and cervical spine (1,6). Results were recorded as positive or negative for each joint. Quantitative evaluation was accomplished with the use of the standard goniometer ARLAN L. ROSENBLOOM, MD MARIA BUITHIEU, MD for the wrist and metacarpalphalangeal KATHLEEN A. JELLIFFE, BSC joints and for flexion of the interphalanROGER D. AITCHISON, SCM geal joints and recorded in degrees of JOSEPH A. TRUGLIA, MD mobility with the use of the Klein device for determining limitation of extension of the interphalangeal joints (6). Bilateral grip strength of the hand This study was undertaken as a ainless and nondisabling limitation was determined using a dynamometer. A of joint mobility (LJM), primarily double-blind placebo-controlled trial of neurological examination was conducted affecting the hands, has been found the aldose reductase inhibitor, ponalrewith the method of Dyck et al. (7). Posin —50% of postadolescent patients with stat (5), in 13 white patients (11 men, 2 tural changes in blood pressure were de>5 yr duration of diabetes, with age be- women), age 18-25 yr, with diabetes termined after 15 min in the supine poing a more important determinant than duration of 6-23 yr. A 1 mo singlesition. Heart rate and blood pressure duration of diabetes, as is also seen with blinded placebo-treated baseline period response to strain were determined in other complications (1). Several studies was followed by 6 mo of double-blinded the nondominant arm while the patient have indicated an approximately fourfold treatment (ponalrestat n = 7, placebo maintained 30% of maximal grip risk of microvascular complications in n = 6) and a 1 mo single-blinded plastrength in the dominant hand. those with LJM as opposed to those with- cebo washout period. Periodic safety and The protocol was approved by out (1-3). Thus, any intervention that efficacy evaluations included a complete the Institutional Review Board of the would reduce LJM could, theoretically, hematologic profile, chemical profile, University of Florida Health Science improve the long-term prognosis for the urinalysis, and physical examination. Center. There were no study withdrawals more serious complications of insulin- Glucose control was assessed by deteror dropouts. mination of glycosylated hemoglobin dependent diabetes mellitus (IDDM). Individual joint measurements Such a possibility was suggested (GHb) concentrations. LJM was staged were summarized into overall scores for by the report of improvement in LJM 1-4 according to established criteria (1) each patient and changes after 6 mo of and patients were randomly assigned with the use of an aldose reductase intreatment using standard parametric t within each of two groups stratified by hibitor, sorbinil, in three patients who tests. These scores were combined to stage of LJM to receive either ponalrestat had substantial functional impairment form an overall efficacy score for the ef(500 mg once daily) or a matching plabut who did not have the syndrome defect on LJM using the rank-sum method scribed in young patients (4). Nonethe- cebo. Patients were instructed to return of O'Brien (8) and comparisons were unused tablets at the next study visit for less, other connective tissue proliferation made by standard t tests. The individual syndromes seen in diabetes might have a determination of compliance, which was overall score for qualitative joint assessvery high. similar biochemical basis to LJM. Were ment was the total number of joints rated this to be true, the milder changes of All examinations were conducted as limited at each assessment. The quanyoung patients with LJM should respond by the same investigator (M.B.). Qualitatitative measurements of extension and most rapidly and dramatically to an in- tive assessment of joint mobility was carflexion were combined to produce an tervention that interrupts the process. ried out as previously described with appropriate single number indicating the arc of motion for each joint. These arc of motion scores were averaged to form a single quantitative joint assessment score FROM THE DIVISION OF ENDOCRINOLOGY, DEPARTMENT OF PEDIATRICS, UNIVERSITY OF FLORIDA COLLEGE for each patient visit. OF MFDICINF, GAINESVILLE, FLORIDA; AND THE ICI PHARMACEUTICALS GROUP, ICI AMERICAS INC., The averaging approach might WILMINGTON, DELAWARE. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO ARLAN L. ROSENBLOOM, MD, J-296 JHMHC, have masked effects of treatment localGAINESVILLE, FL 32610. ized to the joints most affected by LJM,
Effect of an Aldose Reductase Inhibiting Agent on Limited Joint Mobility in ID DM
P
588
DIABETES CARE, VOLUME 15, NUMBER 4, APRIL 1992
Letter
those of digits four and five. Therefore, separate t tests were done to compare changes in extension (the more common limitation) for these digits. Neurological examinations were scored as the sum of three components, muscle strength (0-4), reflexes (0-3), and sensory loss (0-2). The demographics, diabetes duration, and baseline measures of the ponalrestat-treated and placebo assigned groups were comparable except that the two women were randomized to the placebo group. The five efficacy measures (qualitative and quantitative joint scores, grip strength, summed LJM score, and neurological examination score) showed no apparent drug effect during the 6 mo treatment period. Separate analyses of the joints of the fourth and fifth digits failed to unmask a treatment effect. There was also no significant alteration in the response of diastolic blood pressure to hand grip strain in the ponalrestat-treated group compared with the placebo-treated group. No effect on neurological examination scores was noted. Laboratory studies revealed no significant differences between ponalrestattreated and placebo-treated groups for hemoglobin, erythrocyte counts, lymphocyte counts, platelet counts, cell differential, lipid levels, serum total protein, albumin, electrolytes, calcium, phos-
DIABETES CARE, VOLUME 15,
NUMBER 4, APRIL
phate levels, or liver function studies. There was a significant ponalrestatrelated change in serum uric acid level, a decrease of 86.3 |xmol from baseline (mean 253.7 |xmol). After a 1 mo washout, serum uric acid levels approached the level of the baseline mean (mean 268.5 |jimol). No changes were seen in urinalysis in either group. GHb levels increased a mean ± SD of 0.27 ± 1.58% in the ponalrestattreated patients and decreased a mean ± SD of 0.40 ± 1.02% in the placebotreated patients during the 6 mo treatment period, a treatment effect of — 0.67%, which was insignificant. Our patients failed to demonstrate improvement in joint mobility with a 6 -mo trial of a potent aldose reductase inhibitor.
2.
3.
4.
5.
6. Acknowledgments—This study was supported by a grant from ICI Pharmaceuticals Group and by contracts with the Department of Health and Rehabilitative Services of the State of Florida for the Diabetes Research, Education, and Treatment Center, and the Regional Diabetes Program for Children and Youth.
References 1. Rosenbloom AL, Silverstein JH, Lezotte DC, Richardson K, McCallum M: Limited
1992
7.
8.
joint mobility in childhood diabetes indicates increased risk for microvaseular disease. N EnglJ Med 305:191-94, 1981 Kennedy L, Archer DB, Campbell SL, Beacom R, Carson DJ, Johnston PB, Maguire CJ: Limited joint mobility in type 1 diabetes mellitus. Postgrad Med J 54:481-84, 1982 Starkman HS, Gleason RE, Rand LI, Miller DE, Soeldner JS: Limited joint mobility (LJM) of the hand in patients with diabetes mellitus: relation to chronic complications. Ann Rheum Dis 45:130-35, 1986 Eaton RP, Sibbett WL, Harsh A: The effect of an aldose reductase inhibiting agent on limited joint mobility in diabetic patients. JAMA 253:1437-40, 1985 Stribling D, Perkins CM, Smith JC, Uiudadio C: Diabetic neuropathy and its treatment. Drugs Today 25:221-47, 1989 Buithieu M, Rosenbloom AL, Cordon M, Thomas JL, Klein R: Objective measurement of limited joint mobility (LJM) in diabetes (Abstract). Pediatr Res 23:388, 1988 Dyck PJ, Sherman WR, Hallcher LM, Service FJ, O'Brien PC, Grina LA, Palumbo PJ, Swanson CJ: Human diabetic endoneurial sorbitol, fructose and myo-inositol related to sural nerve morphometry. Ann Neurol 8:590-96, 1980 O'Brien PC: Procedures for comparing samples with multiple endpoints. Biometrics 1079-87, 1984
589
