Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.

In vivo deactivation of peripheral, hepatic, and pancreatic insulin action in man.

The in vivo deactivation of insulin action has been studied in 10 lean, nondiabetic subjects using a modification of the euglycemic glucose clamp technique. Following cessation of 40- and 120-mU/m2/min insulin infusions, the serum insulin levels fell to one-half their initial values (mean +/- SE) of 126 +/- 7 and 350 +/- 14 microunits/ml in 7 +/- 1 and 8 +/- 1 min, respectively. The mean incremental glucose disposal rates (IGDR) fell more slowly following discontinuation of the 40- and 120-mU/m2/min insulin infusions, so that the time required for the IGDRs to fall to one-half their initial values (D50 IGDR) were were 42 +/- 5 and 78 +/- 1 min, respectively. Mean hepatic glucose output was totally suppressed during the 40- and 120-mU/m2/min insulin infusions, remained completely suppressed following cessation of the infusions for 50 and 80 mi, and subsequently returned to basal levels. The times required for the HGOs to return to one-half their basal levels (R50 HGO) were 59 +/- 8 and 119 +/- 6 min, respectively. The times required for insulin action to decrease to one-half the initial values in the periphery (D50 IGDR) and in the liver (R50 HGO) were correlated with the preceding steady-state glucose disposal rates in individual subjects (r = 0.75, P less than 0.001 and r = 0.58, P less than 0.05, respectively). The suppression of endogenous insulin secretion by exogenous insulin infusions was also studied in 4 subjects during a total of 5 euglycemic glucose clamps; the mean basal serum C-peptide level was 0.67 +/- 0.24 pmol/ml before administration of the exogenous insulin, fell to 0.34 +/- 0.17 pmol/ml during the steady-state phase of the study, and remained suppressed throughout the duration of the deactivation phase of the glucose clamp. Residual pancreatic insulin secretory capacity was demonstrated by a rise in the serum C-peptide level to 1.77 +/- 0.50 pmol/ml at 120 min following a standardized meal given at the conclusion of the deactivation phase of the glucose clamp. These results demonstrate that the deactivation of insulin action in the periphery, liver, and pancreas lags behind the disappearance of insulin from the plasma. The mechanisms responsible for this lag in in vivo deactivation are not known for certain, but may include slower clearance of insulin form tissue compartments than form the plasma, the necessity for the target tissues to generate specific deactivation signals, or a slow rate of decay of saturable steps in the cellular activation process.

The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects.

Although sulfonylurea agents have been used in the clinical management of type II diabetes (non-insulin-dependent diabetes mellitus, NIDDM) for over two decades, the mechanisms responsible for their hypoglycemic action remain controversial. We have quantitated glycemic control, endogenous insulin secretion in response to mixed meals, adipocyte insulin binding, insulin-mediated peripheral glucose disposal, and basal hepatic glucose output in 17 type II diabetic subjects before and after 3 mo of therapy with the second-generation, sulfonylurea compound glyburide in an attempt to identify the factors responsible for the clinical response to the drug. In addition, 9 subjects were treated for an additional 15 mo to see if the response to the drug changed with time. The mean fasting serum glucose level fell from an initial value of 264 +/- 17 mg/dl to 178 +/- 16 mg/dl after 3 mo of drug therapy. Endogenous insulin secretion increased in all subjects, but the increase was most marked in those subjects who continued to exhibit fasting hyperglycemia (fasting serum glucose greater than 175 mg/dl) after 3 mo of therapy. Adipocyte insulin binding was unchanged after 3 mo of therapy, while the maximal rate of peripheral glucose disposal was increased by 23%, indicating enhancement of peripheral insulin action at a postreceptor site(s). Basal hepatic glucose output showed a significant correlation with the fasting serum glucose level both before and after therapy (r = 0.86, P less than 0.001) and fell from 141 +/- 12 mg/m2/min before therapy to 107 +/- 11 mg/m2/min after 3 mo of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory effect of a growth hormone receptor antagonist (G120K-PEG) on renal enlargement, glomerular hypertrophy, and urinary albumin excretion in experimental diabetes in mice.

Growth hormone (GH) and IGFs have a long and distinguished history in diabetes, with possible participation in the development of renal complications. To investigate the effect of a newly developed GH receptor (GHR) antagonist (G120K-PEG) on renal/glomerular hypertrophy and urinary albumin excretion (UAE), streptozotocin-induced diabetic and nondiabetic mice were injected with G120K-PEG every 2nd day for 28 days. Placebo-treated diabetic and nondiabetic animals were used as reference groups. Placebo-treated diabetic animals were characterized by growth retardation, hyperphagia, hyperglycemia, increased serum GH levels, reduced serum IGF-I, IGF-binding protein (IGFBP)-3, and liver IGF-I levels, increased kidney IGF-I, renal/glomerular hypertrophy, and increased UAE when compared with nondiabetic animals. No differences were seen between the two diabetic groups with respect to body weight, food intake, blood glucose, serum GH, IGF-I, and IGFBP-3 levels or hepatic IGF-I levels. Kidney IGF-I, kidney weight, and glomerular volume were normalized, while the rise in UAE was partially attenuated in the G120K-PEG-treated diabetic animals. No effect of G120K-PEG treatment on any of the parameters mentioned above was seen in nondiabetic animals. In conclusion, administration of a GHR antagonist in diabetic mice has renal effects without affecting metabolic control and circulating levels of GH, IGF-I, or IGFBP-3, thus indicating that the effect of G120K-PEG may be mediated through a direct inhibitory effect on renal IGF-I through the renal GHR. The present study suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease.

The effects of oral fructose, sucrose, and glucose in subjects with reactive hypoglycemia.

We have evaluated the acute effects of orally administered 100-g loads of fructose, sucrose, or glucose given as drinks and of 100-g loads of fructose and sucrose given in cakes on the postprandial serum glucose, insulin, and cortisol responses in seven subjects with reactive hypoglycemia. We defined reactive hypoglycemia as a serum glucose nadir of 65 mg/dl or less, symptoms compatible with hypoglycemia occurring at or after the serum glucose nadir, a hypoglycemic index of greater than 1.0, and a rise in serum cortisol to greater than 20 micrograms/dl after the serum glucose nadir. The data demonstrated that (1) pure fructose given as a drink resulted in relatively flat serum glucose and insulin responses and did not cause a hypoglycemic reaction in any of the subjects, compared with the glucose drink, which caused a hypoglycemic reaction in any of the subjects; (2) ingestion of pure sucrose as a drink elicited significantly flatter serum glucose and insulin responses than did the glucose drink and was associated with some episodes of chemical hypoglycemia and symptoms, but did not result in a hypoglycemic reaction by our definition in any patient; and (3) ingestion of fructose cake led to serum glucose and insulin responses that were lower than those caused by ingestion of sucrose cake, but ingestion of neither fructose nor sucrose cake led to a hypoglycemic reaction by our definition in any patient. In conclusion, the use of fructose as a sweetening agent given either alone, in a drink, or with other nutrients in a cake resulted in markedly flatter serum glucose and insulin responses in subjects with reactive hypoglycemia. Fructose may thus prove useful as a sweetening agent in the dietary treatment of selected patients with reactive hypoglycemia.

Pegvisomant in the treatment of acromegaly.

Epidemiological studies have highlighted the need for tight control of growth hormone (GH) and insulin-like growth factor I (IGF-I) in patients with acromegaly. Studies highlighting the events involved in GH receptor signaling have allowed the development of a pegylated GH receptor antagonist (pegvisomant) for use in humans, which has been designed to outcompete GH for the GH receptor, but which contains a position 120 amino acid substitution that prevents recruitment of a second GH receptor. This process of receptor dimerisation is crucial for signal transduction and IGF-I generation. Clinical trials of pegvisomant suggest it is the most effective treatment for acromegaly to date, as this therapy is capable of normalising serum IGF-I in up to 97% of patients when doses of 40 mg per day are used. This paper reviews the development of pegvisomant and the clinical experience in patients with acromegaly to date.

Growth hormone receptor antagonist therapy in acromegalic patients resistant to somatostatin analogs.

Transsphenoidal surgical resection is the primary therapy for acromegaly caused by GH secreting pituitary adenomas. Medical therapy for patients not controlled by surgery includes primarily somatostatin analogs and secondarily dopamine agonists, both of which inhibit pituitary growth hormone secretion. A novel GH receptor antagonist (pegvisomant) binds to hepatic GH receptors and inhibits peripheral insulin-like growth factor-1 generation. Six patients resistant to maximal doses of octreotide therapy received pegvisomant - three received placebo or pegvisomant 30 mg or 80 mg weekly for 6 weeks and three received placebo and pegvisomant 10-20 mg/d for 12 weeks. Thereafter, all patients received daily pegvisomant injections of doses determined by titrating IGF-1 levels. Serum total IGF-1 levels were normalized in all six acromegalic patients previously shown to be resistant to somatostatin analogs via a novel mechanism of peripheral GH receptor antagonism. The GH receptor antagonist is a useful treatment for patients harboring GH-secreting tumors who are resistant to octreotide.

Insulin treatment reverses the postreceptor defect in adipocyte 3-O-methylglucose transport in type II diabetes mellitus.

The insulin resistance of type II diabetes mellitus is due to both receptor and postreceptor defects of in vivo insulin action, with the postreceptor defect being the predominant abnormality. Diminished glucose transport has been found in adipocytes from patients with type II diabetes, suggesting that decreased cellular glucose transport activity may be responsible in part for the in vivo postreceptor defect observed in these patients. Recent studies have shown that the in vivo postreceptor defect initially present in patients with Type II diabetes is significantly reversed by insulin therapy. For these reasons, we speculated that the defect in adipocyte glucose transport might also be corrected with exogenous insulin therapy. Therefore, we measured adipocyte 3-O-methylglucose transport in cells from five type II diabetic subjects before and after a 2-week period of intensive insulin treatment. Glycemic control was significantly improved by this regimen. The mean (+/- SE) fasting serum glucose level fell from 292 +/- 24 to 135 +/- 29 mg/100 ml (P less than 0.005), and the mean integrated glucose area under a 7-h meal tolerance test curve decreased from 171,212 +/- 20,403 to 72,408 +/- 9,292 mg/min . dl. The mean 3-O-methylglucose transport activity increased after treatment at all insulin concentrations studied, including basal (before, 0.18 +/- 0.05; after, 0.45 +/- 0.09 pmol/2 X 10(5) cells . 10 sec; P less than 0.005) and maximally effective (25 ng/ml) insulin concentrations (before, 0.50 +/- 0.14; after, 1.32 +/- 0.30 pmol/2 X 10(5) cells . 10 sec; P less than 0.025), although the mean maximal glucose transport activity was still 25% decreased compared to normal values, indicating that a residual in vitro postreceptor defect remained. These results corresponded well with the degree of reversal (75%) of the in vivo postreceptor defect, as assessed by the euglycemic glucose clamp technique. These studies demonstrated that the decrease in adipocyte glucose transport activity in type II diabetes is practically reversible by intensive insulin therapy. This closely corresponds to the reversal by insulin therapy of the postreceptor defect expressed in vivo and provides further evidence that a cellular cause of the postreceptor defect in type II diabetes is a decrease in glucose transport system activity in the major insulin target tissues.

Lack of in vivo insulin resistance in controlled insulin-dependent, type I, diabetic patients.

Although type I diabetic patients are clearly insulin deficient, it is unclear whether they have normal in vivo sensitivity to insulin. Recent studies which suggested that insulin resistance is a common feature of insulin-dependent diabetics have not taken into account their degree of metabolic control or the presence of circulating antibodies. In the present study, we performed multiple euglycemic glucose clamp studies to construct insulin dose-response curves in 5 well controlled and 5 poorly controlled type I diabetic patients and 21 age-matched normal subjects. Each study was performed on a separate day at insulin infusion rates of 15, 40, 120, 240, or 1200 mU/M2 X min. During the 40 and 120 mU/M2 X min infusions, steady state insulin levels of 96 +/- 8 (+/- SE) and 285 +/- 27 microU/ml respectively, were achieved within 25 min in normal subjects. In contrast, diabetic subjects did not achieve steady state insulin levels (62 +/- 8 and 212 +/- 16 microU/ml) until 90 min of infusion, and insulin antibodies were detectable in the serum of all these patients. The dose-response curve for insulin stimulation of glucose disposal in well controlled diabetic subjects was comparable to that in normal subjects, with half-maximally effective insulin levels of 84 microU/ml in the diabetic patients compared to 70 microU/ml in normal subjects and virtually identical maximal rates of glucose disposal (433 +/- 11 vs. 411 +/- 17 mg/M2 X min in controls). In contrast, the dose-response curve for poorly controlled diabetic subjects was significantly right-shifted (half-maximally effective insulin level, 112 microU/ml), with marked reduction in the maximal glucose disposal rate (324 +/- 25 vs. 411 +/- 17 mg/M2 X min in normal subjects). Basal hepatic glucose output was increased in both poorly controlled and well controlled type I diabetic patients (132 +/- 7 and 101 +/- 16 mg/M2 X min, respectively) compared to normal subjects (76 +/- 7 mg/M2 X min). However, during each insulin infusion, hepatic glucose output was virtually 100% suppressed in all 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Control of tumor size and disease activity during cotreatment with octreotide and the growth hormone receptor antagonist pegvisomant in an acromegalic patient.

We describe the case of an acromegalic subject, who was the first patient ever treated with the GH receptor antagonist pegvisomant. Furthermore, in this particular patient, progression in tumor size was encountered during treatment with pegvisomant. The patient described did benefit from cotreatment with pegvisomant and octreotide, including decreased GH levels, normalization of serum insulin-like growth factor I concentrations, and improvement of visual field defects.

Insulin resistance and diabetes due to a genetic defect in insulin receptors.

A 14-yr-old woman presented with fasting hyperglycemia (269 mg/dl), fasting hyperinsulinemia (45 microU/ml), acanthosis nigricans, and insulin resistance. The patient's circulating insulin was normal by physical and biological criteria, and insulin receptor antibodies were not detected. Both the patient's in vivo dose-response curve for insulin-stimulated glucose transport in isolated adipocytes were shifted to the right and showed marked decreases in the maximal insulin response. Basal hepatic glucose output was significantly increased, and the in vivo dose-response curve for insulin-mediated suppression of basal hepatic glucose output was shifted to the right. Insulin binding to the patient's erythrocytes, monocytes, and adipocytes was markedly decreased. To confirm that the severe reduction in cellular insulin receptors was a primary rather than an acquired defect, similar studies were conducted using cultured fibroblasts. No detectable binding of insulin to these cells was observed. Further studies showed that the patient's mother and two sisters were hyperinsulinemic and insulin resistant, and had comparable, although less severe, changes in insulin binding. The patient was also demonstrated to have an insulin secretory defect both to both oral and iv glucose challenges. We thus conclude that this family demonstrates a genetic deficiency of insulin receptors, resulting in insulin resistance and, in this patient, severe diabetes mellitus.

Acute effect of ascorbic acid infusion on carbohydrate tolerance.

Large doses (1 to 2g/3 hr) of ascorbic acid were administered intravenously to normal weight and obese, nondiabetic subjects. Glucose tolerance and fasting plasma glucose levels were unaffected, despite a 3- to 8-fold rise in plasma concentrations of the vitamin. Infusion of ascorbic acid did not alter fasting serum insulin levels in normal subjects, but was associated with lower concentrations of hormone during an intravenous glucose tolerance test. Plasma glucose, serum insulin, growth hormone, and glucagon levels in obese subjects remained unchanged during the ascorbic acid infusion.

Comparison of the metabolic responses to fructose and sucrose sweetened foods.

We studied the acute effects of oral ingestion of fructose and sucrose sweetened cakes and ice creams on postprandial serum glucose and insulin responses in 10 normal subjects, six subjects with impaired glucose tolerance, and 10 noninsulin-dependent diabetic subjects. The data demonstrate that: 1) ingestion of fructose cakes and ice creams resulted in lower serum glucose and insulin responses than did the sucrose cakes and ice creams in all study groups; 2) when comparing cakes to ice creams, the serum glucose and insulin responses after ice cream ingestion were lower than responses after cake ingestion. In conclusion, when fructose is incorporated as a sweetener in a complex food product, it is associated with significantly lower serum glucose and insulin responses as compared to comparable sucrose sweetened foods.

Behçet's syndrome. Report of a case associated with pericardial effusion and cryoglobulinemia treated with indomethacin.

A patient with Behçet's syndrome manifested by optic atrophy, purulent conjunctivitis and orogenital ulcerations presented with a high fever and pericardial effusion. A mixed cryoglobulinemia (immunoglobulin A (IgA)-immunoglobulin G (IgG)) was observed. Treatment with indomethacin resulted in rapid defervescence, resolution of the pericardial effusion and the orogenital ulcerations, and disappearance of the cryoglobulinemia. Discontinuation of indomethacin therapy was followed by a recurrence of the oral and genital ulcerations that responded promptly to the reinstitution of indomethacin treatment.

Antitumor activity of the growth hormone receptor antagonist pegvisomant against human meningiomas in nude mice.

OBJECT: The authors have previously demonstrated that modulation of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis can significantly affect meningioma growth in vitro. These studies were performed to evaluate the efficacy of GH receptor blockade in vivo. METHODS: Primary cultures from 15 meningioma tumors obtained in humans were xenografted into athymic mice. Approximately 1.5 million cells from each of the 15 tumors were implanted into the flanks of two female mice, one pair for each tumor. One animal from each of the 15 pairs was then treated with the GH receptor antagonist pegvisomant and the other with vehicle alone for 8 weeks. The tumor volume was measured using digital calipers three times per week. The mean tumor volume at the initiation of injections was 284 +/- 18.8 mm3 in the vehicle group and 291.1 +/- 20 mm3 in the pegvisomant group. After 8 weeks of treatment, the mean volume of tumors in the pegvisomant group was 198.3 +/- 18.9 mm3 compared with 350.1 +/- 23.5 mm3 for the vehicle group (p < 0.001). The serum IGF-I concentration in the vehicle group was 319 +/- 12.9 microg/L compared with 257 +/- 9.7 in the pegvisomant group (p < 0.02). A small but significant decrease was observed in circulating IGF binding protein (IGFBP)-3 levels, whereas slight increases occurred with respect to serum IGFBP-1 and IGFBP-4 levels. In the placebo group the tumor weight was 0.092 +/- 0.01 g compared with 0.057 +/- 0.01 g in the pegvisomant group (p < 0.02). The IGF-I and IGF-II concentrations were measured in the tumors by using a tissue extraction method. These human-specific immunoassays demonstrated that there was no autocrine production of IGF-I in any of the tumors, either in the pegvisomant or vehicle group. The IGF-I levels were highly variable (0-38.2 ng/g tissue) and did not differ significantly between treatment groups. CONCLUSIONS: In an in vivo tumor model, downregulation of the GH/IGF-I axis significantly reduces meningioma growth and, in some instances, causes tumor regression. Because the concentrations of IGF-II in tumor did not vary with pegvisomant treatment and there was no autocrine IGF-I production by the tumors, the mechanism of the antitumor effect is most likely a decrease of IGF-I in the circulation and/or surrounding host tissues. Because the authors have previously demonstrated that the GH receptor is ubiquitously expressed in meningiomas, direct blockade of the GH receptor on the tumors may also be contributing to inhibitory actions.

Insulin resistance in non-insulin dependent (type II) and insulin dependent (type I) diabetes mellitus.

Insulin resistance is a characteristic feature of non-insulin dependent diabetes mellitus (NIDDM) due to target tissue defects in insulin action. Abnormalities of cellular insulin action can be divided into receptor and post-receptor defects. Patients with impaired glucose tolerance are insulin resistant due to decreased insulin receptors resulting in decreased insulin sensitivity and rightward shifted in vivo dose response curves. Patients with NIDDM are insulin resistant due to a combination of receptor and post-receptor defects. The greater the severity of the diabetes (greater fasting hyperglycemia) the greater the post-receptor defect, and in those patients with more significant fasting hyperglycemia the post-receptor defect is the predominant abnormality leading to the insulin resistant state. At least one of the abnormalities underlying this post-receptor defect involves a decrease in glucose transport system activity in freshly isolated adipocytes. This defect in glucose transport, is not expressed in cultured fibro-blasts, indicating that the abnormality in glucose disposal seen in vivo and in glucose transport seen in freshly isolated cells is an acquired phenomenon. Consistent with this, the post-receptor defect is partially reversible by insulin therapy, which leads to a 50-70% reversal of the reduced rates of in vivo glucose disposal and in vitro glucose transport. Insulin resistance also exists in poorly controlled IDDM patients, due to a postreceptor defect in insulin action. This insulin resistance is not present in well controlled IDDM patients, and is completely reversible when poorly controlled patients are treated with intensive insulin therapy. Insulin is produced in the pancreatic beta cell as the primary biosynthetic product preproinsulin. This peptide is rapidly converted to proinsulin (MW approximately 9000). Proinsulin is converted to insulin (MW approximately 6000) plus C-peptide in the secretory granule with a small amount (approximately 5 percent) of the proinsulin remaining unconverted. After a brief time in the peripheral circulation (half-life six to 10 minutes), insulin interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is the promotion of overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states including Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM). Since insulin travels from the beta cell through the circulation to the target tissues, abnormalities at any of these loci can influence the ultimate action of the hormone. These abnormalities, all

Amiprilose hydrochloride for rheumatoid arthritis.

STUDY OBJECTIVE: To assess the safety and efficacy of amiprilose hydrochloride (HCl), a novel synthetic carbohydrate with anti-inflammatory and immunomodulatory properties, in patients with rheumatoid arthritis. DESIGN: Prospective, multicenter, randomized, parallel group, double-blind placebo-controlled 12-week trial. PATIENTS: Two hundred and one functional class I and II patients with definite or classic rheumatoid arthritis, previously untreated with disease modifying antirheumatic drugs. INTERVENTIONS: Patients were withdrawn from nonsteroidal anti-inflammatory drug therapy. Those who flared were randomly assigned to amiprilose HCl, 6 g/d, or placebo for 12 weeks. No concomitant anti-inflammatory or antirheumatic drug therapy was permitted during the study. Combination acetaminophen and propoxyphene napsylate was the only supplemental analgesic medication allowed. MEASUREMENTS AND MAIN RESULTS: The number of painful joints and swollen joints, joint pain and joint swelling indices, left and right grip strength, investigator global assessment, and patient global assessment returned to baseline for the amiprilose group and showed statistically significant (P less than 0.05) differences from the placebo group within 4 to 6 weeks. The protocol criteria for overall therapeutic response were satisfied by 41% of the amiprilose patients, compared with 21% of the placebo group (P = 0.003). Approximately 0.5 tablet per day less analgesic medication was taken by the amiprilose group (P less than 0.05 at weeks 6 and 12). There were no statistically significant differences in morning stiffness, walking time, erythrocyte sedimentation rate, C-reactive protein, or rheumatoid factor between the groups. A similar number of adverse experiences were reported by the patients on amiprilose (67%) and on placebo (63%). One patient on amiprilose developed thrombocytopenia of unknown cause; no other reported adverse effects were serious. CONCLUSIONS: Amiprilose HCl has significant anti-inflammatory activity and a favorable safety profile when used as the sole antirheumatic therapy in patients with active rheumatoid arthritis. Synthetic carbohydrates may represent an important new class of drugs for the treatment of inflammatory, autoimmune diseases.