Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk.

AIMS: Mixed dyslipidaemia, characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides, is common in patients with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome. Dalcetrapib effectively increases HDL-C levels by modulating cholesteryl ester transfer protein (CETP) activity. The aim of this analysis was to investigate the lipid modifying efficacy and safety of dalcetrapib in patients with T2DM and/or metabolic syndrome. METHODS: Post hoc analysis of dalcetrapib therapy in five placebo-controlled, Phase II trials (4-48 weeks of duration) involving T2DM and/or metabolic syndrome, in dyslipidaemic patients with coronary heart disease (CHD) or CHD risk equivalent. RESULTS: Both in patients with and without T2DM and/or metabolic syndrome, dalcetrapib decreased CETP activity by 26-58% and increased HDL-C levels by 23-34%, depending on dose and duration of treatment. Dalcetrapib did not significantly affect low-density lipoprotein cholesterol (LDL-C) or apolipoprotein B levels. Treatment with dalcetrapib was generally well tolerated with a similar number of adverse events reported between patient groups and between those receiving dalcetrapib compared with placebo. CONCLUSIONS: Dalcetrapib similarly decreased CETP activity and increased HDL-C levels in patients with and without T2DM or metabolic syndrome; the ongoing Phase III dal-OUTCOMES study will help to determine if dalcetrapib's improvement in lipid levels also reduces cardiovascular morbidity and mortality.

Biodritin microencapsulated human islets of Langerhans and their potential for type 1 diabetes mellitus therapy.

BACKGROUND: Microencapsulation of pancreatic islets with polymeric compounds constitutes an attractive alternative therapy for type 1 diabetes mellitus. The major limiting factor is the availability of a biocompatible and mechanically stable polymer. We investigated the potential of Biodritin, a novel polymer constituted of alginate and chondroitin sulfate, for islet microencapsulation. METHODS: Biodritin microcapsules were obtained using an air jet droplet generator and gelated with barium or calcium chloride. Microencapsulated rat insulinoma RINm5F cells were tested for viability using the [3-(4,5-dimetyl-thiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide] [MTT] colorimetric assay. Microencapsulated rat pancreatic islets were coincubated with macrophages derived from mouse peritoneal liquid to assess the immunomodulatory potential of the microcapsules, using quantitative real time-PCR (qPCR). Biodritin biocompatibility was demonstrated by subcutaneous injection of empty microcapsules into immunocompetent Wistar rats. Insulin secretion by microencapsulated human pancreatic islets was evaluated using an electrochemoluminescent assay. Microencapsulated human islets transplanted into chemically induced diabetic mice were monitored for reversal of hyperglycemia. RESULTS: The metabolic activity of microencapsulated RINm5F cells persisted for at least 15 days. Interleukin-1beta expression by macrophages was observed during coculture with islets microencapsulated with Biodritin-CaCl2, but not with Biodritin-BaCl2. No statistical difference in glucose-stimulated insulin secretion was observed between nonencapsulated and microencapsulated islets. Upon microencapsulated islet transplantation, the blood glucose level of diabetic mice normalized; they remained euglycemic for at least 60 days, displaying normal oral glucose tolerance tests. CONCLUSION: This study demonstrated that Biodritin can be used for islet microencapsulation and reversal of diabetes; however, further investigations are required to assess its potential for long-term transplantation.

Prolactin-induced changes in protein expression in human pancreatic islets.

Ex vivo islet cell culture prior to transplantation appears as an attractive alternative for treatment of type 1 diabetes. Previous results from our laboratory have demonstrated beneficial effects of human prolactin (rhPRL) treatment on human islet primary cultures. In order to probe into the molecular events involved in the intracellular action of rhPRL in these cells, we set out to identify proteins with altered expression levels upon rhPRL cell treatment, using two-dimensional (2D) gel electrophoresis and mass spectrometry (MS). An average of 300 different protein spots were detected, 14 of which were modified upon rhPRL treatment (p<0.01), of which 12 were successfully identified using MS and grouped according to their biological functions. In conclusion, our study provides, for the first time, information about proteins that could be critically involved in PRL's action on human pancreatic islets, and facilitate identification of new and specific targets involved in islet cell function and proliferation.

HLA-DRB1 alleles in juvenile-onset systemic lupus erythematosus: renal histologic class correlations.

Human leukocyte antigens (HLA) DRB1*03 and DRB1*02 have been associated with systemic lupus erythematosus (SLE) in Caucasians and black populations. It has been observed that certain HLA alleles show stronger associations with SLE autoantibodies and clinical subsets, although they have rarely been associated with lupus renal histologic class. In the present study, HLA-DRB1 allele correlations with clinical features, autoantibodies and renal histologic class were analyzed in a cohort of racially mixed Brazilian patients with juvenile-onset SLE. HLA-DRB1 typing was carried out by polymerase chain reaction amplification with sequence-specific primers using genomic DNA from 55 children and adolescents fulfilling at least four of the American College of Rheumatology criteria for SLE. Significance was determined by the chi-square test applied to 2 x 2 tables. The HLA-DRB1*15 allele was most frequent in patients with renal, musculoskeletal, cutaneous, hematologic, cardiac, and neuropsychiatric involvement, as well as in patients positive for anti-dsDNA, anti-Sm, anti-U1-RNP, and anti-SSA/Ro antibodies, although an association between HLA alleles and SLE clinical features and autoantibodies could not be observed. The HLA-DRB1*17, HLA-DRB1*10, HLA-DRB1*15, and HLA-DRB1*07 alleles were significantly higher in patients with renal histologic class I, class IIA, class IIB, and class V, respectively. The present results suggest that the contribution of HLA- DRB1 alleles to juvenile-onset SLE could not be related to clinical or serological subsets of the disease, but it may be related to renal histologic classes, especially class I, class II A, class II B, and class V. The latter correlations have not been observed in literature.

Increased hepatitic cholesterol production due to liver hypertrophy in rat experimental nephrosis.

Control and nephrotic rats were compared as to the liver contents of cholesterol, phospholipid and the activity of microsomal 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Whole liver homogenates as well as endoplasmic reticulum membrane samples showed increased free cholesterol and phospholipid mass in the nephrotics. Correction of the values by the protein content indicated membrane expansion, i.e. liver hypertrophy. However, total hepatic cholesterol synthesis as measured by the reductase activity was increased in the nephrotic rat. These results are in accordance with previous studies showing enhanced cholesterol production in experimental nephrosis. In short, enhanced cholesterol mass in the liver coexists with increased hepatic synthesis in the experimental model used.

Characterization of somatomedin binding in human serum by ultracentrifugation and gel filtration.

It is known that the somatomedins exist in human serum complexed to specific binding proteins. The existence of unbound somatomedins in serum has never unequivocally been demonstrated. We have characterized the distribution of insulin-like growth factor (IGF) I in different fractions after gel filtration of serum through Sephadex G-200 in neutral buffer. IGF-I was measured by RIA after acid extraction. Seventy-two percent of serum IGF-I was associated with large complexes with an estimated size of about 150,000 daltons and 25% was associated with smaller complexes of about 50,000 daltons. No unbound IGF-I was detected. Ultracentrifugation of 10 ml fresh serum was carried out at 106,000 X g for 17 h, after which the tube was aspirated in 1-ml fractions beginning at the top. IGF-I by RIA in fractions 2 and 3 sedimented with albumin; in fractions 4 to 7, the sedimentation pattern approached that of immunoglobulin G. This shift is consistent with the size distribution of IGF-I complexes demonstrated by gel filtration. The failure to find any significant increase in the concentration of IGF-I relative to albumin in the top 30% of the tube (fractions 1-3) after centrifugation argues against the presence of measurable free IGF-I in these fractions. The ability of upper fractions to bind added [125I]IGF-II proved to closely approximate the binding of the initial serum, indicating little sedimentation of the accessible binding protein. The relative binding of [125I]IGF-II by serum aliquots proved to be markedly concentration dependent. At concentrations above 5% serum, the incremental increase of binding as a function of serum concentration was much reduced. We interpret this to indicate that with dilution there is a dissociation of complexes and an increase in accessible binding sites. This phenomenon may modify tissue delivery of somatomedins in interstitial fluid. The data suggest that in undiluted serum there is no significant concentration of free somatomedins but at the dilution of serum that exists in the interstitial fluid, dissociation of bound somatomedins may be facilitated.

A novel missense mutation, GLY424SER, in Brazilian patients with 21-hydroxylase deficiency.

A previous screening of 17 mutations in 130 Brazilian patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency did not identify mutations in 20% of the alleles. To diagnose these alleles we sequenced the entire CYP21 gene of one Mulatto patient with the simple virilizing form, who had only the R356W mutation in a heterozygous state. We identified a heterozygous G-A transition in codon 424. This mutation leads to a substitution of glycine by serine in a conserved region where glycine is conserved in at least 4 species. This novel mutation eliminates 1 of the restriction sites of the BanI enzyme, which made its screening possible for the whole series. The G424S mutation was found in a compound heterozygous state in 5 families; 4 presented the simple virilizing form, and 1 presented the nonclassical form. Interestingly, 3 of 5 families have a Mulatto origin. This mutation was not identified in 118 CYP21 alleles of normal individuals, ruling out the possibility of a polymorphism, or in 80 pseudogenes, indicating a casual mutagenic event and not a microconversion event. All patients with the G424S mutation presented CYP21P and C4A gene deletions and human leukocyte antigen DR17 on the same haplotype, suggesting a linkage disequilibrium and a probable founder effect. Search for the G424S mutation in other populations will reveal whether it is restricted to the Brazilian patients or if it has a wider ethnic distribution.

HLA and beta-myosin heavy chain do not influence susceptibility to Chagas disease cardiomyopathy.

An inflammatory dilated cardiomyopathy occurs in 30% of Chagas' disease patients, chronically infected by Trypanosoma cruzi, while the remaining infected individuals are asymptomatic. Studies have indicated a role for genetic factors in the susceptibility to Chagas' disease cardiomyopathy. In an attempt to identify the genetic factors influencing the development and outcome of Chagas' cardiomyopathy, we compared the frequencies of alleles from two candidate gene loci, class II HLA and a microsatellite marker for the human cardiac beta-myosin heavy chain gene in different clinical groups. Patients were grouped as asymptomatic or with severe or mild cardiomyopathy. The results indicate that the HLA and myosin microsatellite allele profiles in all cardiomyopathy and in asymptomatic groups are similar. In conclusion, these results establish that polymorphism of HLA-DR and -DQ molecules, as well as beta-cardiac myosin, do not influence the susceptibility to different clinical forms of Chagas' disease or the progression to severe Chagas' cardiomyopathy. On the other hand, male sex was identified as a risk factor for progression to the more severe forms of cardiomyopathy (relative risk = 8.75).

Double-blind comparison of bezafibrate versus placebo in male volunteers with hyperlipoproteinemia.

The efficacy and safety of bezafibrate were evaluated in 83 patients with type IIa, IIb, or IV hyperlipoproteinemia. Following a 12- to 14-week placebo period on a coronary-prudent diet (Period 1), patients were assigned randomly to receive either bezafibrate 600 mg/day or placebo, plus diet in a double-blind, 12-week treatment period (Period 2). The return of lipid and lipoprotein levels toward baseline was evaluated in a subsequent 8-week period on placebo plus diet (Period 3). In patients with type IIa hyperlipoproteinemia, bezafibrate significantly lowered total (14.6%, P less than 0.001) and LDL-cholesterol (16.4%, P less than 0.001) and total (29.9%, P less than 0.001) and VLDL-triglyceride (44.0%, P less than 0.001) and significantly increased HDL cholesterol (9.5%, P less than 0.001). In patients with type IIb, bezafibrate had a qualitatively similar effect to that seen in type IIa on each of these lipoproteins, but the sample size was too small for statistical evaluation. In patients with type IV, bezafibrate lowered total (48.3%, P less than 0.01) and VLDL-triglyceride (57.7%, P less than 0.001) and VLDL-cholesterol (56.8%, P less than 0.001) and increased HDL-cholesterol (16.6%, P less than 0.05). All values returned toward baseline during Period 3. Only two bezafibrate patients experienced adverse events that were considered definitely treatment related; one was dropped from the study because of elevations in SGOT and SGPT, 1.5- and 4-times the upper limit of normal, respectively. For other laboratory parameters, trends upward or downward were small and of doubtful clinical significance. Bezafibrate appears to be effective and safe for modifying lipid and lipoprotein levels in patients with types IIa, IIb and IV hyperlipoproteinemia.

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. II. Once-daily versus twice-daily dosing.

This 8-week multicenter, placebo-controlled trial compared the efficacy and safety of the HMG-CoA reductase inhibitor, pravastatin, when administered either as single doses of 40 mg in the morning (AM) or evening (PM) or 20 mg twice daily (bid) in 196 diet-stabilized outpatients with primary type II hypercholesterolemia. Mean reductions in total and low-density lipoprotein (LDL) cholesterol concentrations were observed in all pravastatin groups after 1 week and were sustained throughout the study (P less than or equal to 0.001 versus baseline and placebo). At week 8, mean reductions from baseline in the pravastatin treatment groups were 23-27% for total cholesterol and 30-34% for LDL cholesterol. LDL cholesterol was reduced greater than or equal to 15% by pravastatin in all patients in the group treated with 40 mg PM and in 88 and 96% in those receiving 20 mg bid and 40 mg AM, respectively. High density lipoprotein cholesterol was elevated (up to 8%) and triglycerides were reduced (up to 25%) by all pravastatin regimens (P less than or equal to 0.05). Pravastatin was well tolerated and was associated with a low incidence of adverse events. No patient withdrew from the study due to a pravastatin-related adverse event. Once-daily pravastatin is a safe and effective treatment for patients with primary hypercholesterolemia and has a favorable safety profile.

The effects of colestipol tablets compared with colestipol granules on plasma cholesterol and other lipids in moderately hypercholesterolemic patients.

The purpose of this study was to investigate and compare the efficacy, safety, and patient acceptability of a new formulation of colestipol, colestipol tablets (T), with those of colestipol granules (G), in a randomized, double-blind, placebo-controlled, multicenter study. Three hundred and seventeen patients with primary hypercholesterolemia who were following a low-fat, low-cholesterol diet (NCEP Step I diet), and had low-density lipoprotein cholesterol (LDL-C) levels > or = 4.14 mmol/l (160 mg/dl) and < or = 6.46 mmol/l (250 mg/dl) were studied. Study medication was taken twice a day, with breakfast and supper, for 8 weeks. The six parallel treatment groups consisted of colestipol tablets 2 g b.i.d. and 8 g b.i.d., matching placebo tablets b.i.d., colestipol granules 2 g b.i.d. and 8 g b.i.d., and matching placebo granules b.i.d.. Study endpoints included absolute change and percentage change from baseline in selected lipid, lipoprotein, and apolipoprotein measurements; LDL-C lowering was the primary efficacy endpoint. Treatment with colestipol tablets and colestipol granules resulted in virtually identical, statistically significant (P < or = 0.05) reductions of LDL-C, total cholesterol (TC), TC/HDL-C, and apolipoprotein B (apo B). Compared with placebo, all active treatments (tablets 4 g/day, tablets 16 g/day, granules 4 g/day, granules 16 g/day) significantly reduced LDL-C (12%, 24%, 12%, 25%, respectively), TC (7%, 15%, 8%, 15%, respectively), TC/HDL-C (8%, 14%, 9%, 15%, respectively) and apo B (12%, 20%, 13%, 22%, respectively). All active treatments significantly increased lipoprotein particle AI (LpAI) (5%, 23%, 14%, 18%, respectively). VLDL-C and triglycerides increased significantly in the high-dose groups. The proportions of patients reporting adverse events, largely gastrointestinal-related, were not different among the active treatment groups. The treatments were well-tolerated, and no drug-related serious adverse events were reported. Patients experienced with granule medication prior to this study preferred tablets over granules. This study demonstrates that colestipol tablets are an effective treatment to reduce LDL-C in patients with primary hypercholesterolemia, are equivalent to colestipol granules, are well-tolerated, and are preferred over granules by patients.

Efficacy and safety of pravastatin in patients with primary hypercholesterolemia. I. A dose-response study.

This multicenter, double-blind, placebo-controlled, dose-response study was conducted in patients with primary hypercholesterolemia to examine the effects of pravastatin, a selective inhibitor of HMG-CoA reductase, on plasma lipids and lipoproteins. A total of 306 patients on cholesterol-lowering diets received twice daily doses of 5 mg, 10 mg, 20 mg pravastatin, or placebo for 12 weeks. Marked reductions in low density lipoprotein (LDL) cholesterol and total cholesterol were observed after 1 week of treatment; maximum lipid-lowering effects occurred at 4 weeks and were sustained for the duration of the trial. At week 12, pravastatin treatment resulted in dose-dependent mean reductions from baseline in LDL cholesterol of 17.5%, 22.9%, and 30.8% for the 3 doses tested (P less than or equal to 0001 compared with baseline and placebo). The reduction in LDL cholesterol was log-linear with respect to dose; each doubling of dose reduced LDL cholesterol an additional 6.5%. Dose-dependent reductions in total cholesterol from 12.9% to 23.3% also occurred (P less than or equal to 0.001). Triglycerides decreased by as 15.4% (P less than or equal to 0.001) and high-density lipoprotein (HDL) cholesterol increased approximately 7% (P less than or equal to 0.01), but these effects were not dose-dependent. No patient receiving pravastatin was discontinued during the 12-week trial. Transient episodes of rash and headache occurred. Slight increases in mean serum levels of ASAT and ALAT occurred, and 2% of both placebo- and pravastatin-treated patients reported myalgia although there was no clinically significant elevation of creatine kinase. These data indicate that pravastatin favorably affects all lipid parameters and is well tolerated.

Fenofibrate affects the compositions of lipoproteins.

This study assessed the effects of fenofibrate on lipoprotein levels and lipoprotein compositions in a subgroup of patients who participated in a multicenter fenofibrate study. Eleven men and 10 women aged 29 to 63 were studied, 12 with type II A and nine with type II B hyperlipoproteinemia. Fasting blood samples were obtained every four to six weeks. Lipoprotein lipids were quantified by procedures of the Lipid Research Clinics, and apolipoproteins by radioimmunoassay. Fenofibrate decreased mean triglyceride and cholesterol levels of the type II A patients from 130 to 99 and from 286 to 237 mg/dl, respectively. Levels of very low-density lipoprotein triglycerides, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol decreased and high-density lipoprotein cholesterol levels rose. Apolipoprotein B and apolipoprotein E levels decreased, whereas apolipoprotein AI and apolipoprotein AII levels rose. The mean very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratio and low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratio decreased. The low-density lipoprotein cholesterol:apolipoprotein B ratio and high-density lipoprotein cholesterol: apolipoprotein AII ratio decreased as did the apolipoprotein AI:apolipoprotein AII ratio. In patients with type II B hyperlipoproteinemia, triglyceride and cholesterol levels decreased with fenofibrate therapy with most of the decrease in triglyceride levels due to very low-density lipoprotein triglycerides, whereas the decrease in total cholesterol levels was due to decreases in very low-density lipoprotein and low-density lipoprotein cholesterol. High-density lipoprotein cholesterol levels rose. The decrease in low-density lipoprotein cholesterol levels was not significant in this group. Apolipoprotein E levels decreased and apoliprotein AI and apolipoprotein AII levels rose. Indices of composition in type II B patients were similar to those in type II A patients but the changes were less dramatic. Very low-density lipoprotein cholesterol:very low-density lipoprotein triglyceride ratios decreased significantly, but low-density lipoprotein cholesterol:low-density lipoprotein triglyceride ratios did not change significantly with treatment. The mean low-density lipoprotein cholesterol:apolipoprotein B ratio, high-density lipoprotein cholesterol:apolipoprotein AII ratio, and apolipoprotein AI:apolipoprotein AII ratio all were lowered by therapy. Thus, very low-density lipoprotein and low-density lipoprotein lost cholesterol in response to fenofibrate therapy and high-density lipoprotein particles became enriched in cholesterol.

Effects of fenofibrate on plasma lipoproteins in hypercholesterolemia and combined hyperlipidemia.

To investigate the lipoprotein effect of fenofibrate in hypercholesterolemia or combined hyperlipidemia (types II A and II B hyperlipidemias, respectively), 240 patients were recruited and 227 randomized to a double-blind randomized trial lasting 24 weeks and 192 patients continued to participate in an open-label phase for another 24 weeks. A 100-mg dose of fenofibrate or a matching placebo was given three times daily. Fenofibrate side effects in excess of placebo affected 6 percent of fenofibrate users and were confined almost entirely to skin rashes. In 180 hypercholesterolemic patients randomly assigned to receive fenofibrate versus placebo, triglyceride and very low-density lipoprotein cholesterol levels decreased 38 percent, total cholesterol levels decreased 17.5 percent, and low-density lipoprotein cholesterol levels decreased 20.3 percent with fenofibrate treatment. High-density lipoprotein cholesterol levels increased 11.1 percent with a decrease in the low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio of 27 percent. All differences were statistically significant (p less than 0.01). In combined hyperlipidemic (type II B) patients, triglyceride levels decreased by 45 percent, very low-density lipoprotein cholesterol levels decreased 52.7 percent, total cholesterol levels decreased 16 percent, low-density lipoprotein cholesterol levels decreased 6 percent, and high-density lipoprotein levels increased 15.3 percent for a low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratio decrease of 13 percent. All differences were again statistically significant (p less than 0.01). In both groups of patients, the onset of the drug effect was generally rapid, with maximal total and low-density lipoprotein cholesterol level lowering achieved within four weeks in hypercholesterolemic patients and maximal triglyceride and cholesterol level lowering in hypertriglyceridemic patients achieved in two weeks. Maximum high-density lipoprotein increases occurred after four weeks in type II A patients and 12 to 16 weeks in type II B patients. Fenofibrate is a well-tolerated drug in the fibric acid series and has putatively beneficial effects on triglyceride, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein cholesterol concentrations in both type II A and type II B hyperlipidemic patients. If the lipid hypothesis of atherosclerosis applies to the lipoprotein changes induced by fenofibrate, reductions in cardiovascular disease risk in both type II A and II B hyperlipidemic patients should result from fenofibrate treatment.

Clinical trial experience with extended-release niacin (Niaspan): dose-escalation study.

Niacin is a useful lipid-modifying drug because it (1) decreases low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, and lipoprotein(a), and (2) raises high-density lipoprotein (HDL) cholesterol. Its use tends to be limited by side effects and inconvenient dosing regimens. The availability of an extended-release preparation (Niaspan-which has safety and efficacy similar to immediate-release niacin but which can be given once a day) provides an opportunity to increase the use of this effective lipid-modifying agent. To study the safety and efficacy of escalating doses of extended-release niacin, hyperlipidemic patients were randomly assigned to placebo or Niaspan. A forced dose-titration was done with the dosage increasing by 500 mg every 4 weeks to a maximum of 3,000 mg/day. Niaspan showed dose-related changes in total, LDL, and HDL cholesterol levels, triglycerides, cholesterol/HDL ratio, and lipoprotein(a). At a dosage of 2,000 mg/day, total cholesterol decreased by 12.1%, LDL cholesterol by 16.7%, triglycerides by 34.5%, and lipoprotein(a) by 23.6%; HDL cholesterol increased by 25.8%. Flushing was the most commonly reported side effect; flushing episodes tended to decrease with time despite an increasing dose of niacin. Of the reported side effects, only pruritus and rash were significantly different between the 2 groups. Aspartate aminotransferase, lactate dehydrogenase, and uric acid increased in a dose-dependent fashion, but fasting blood sugar increased by about 5% across most dosages. Two subjects had aspartate aminotransferase levels greater than twice the upper limit of normal, but there were no subjects in whom transaminases increased to 3 times the upper limit of normal. Women tended to have a greater LDL cholesterol response to the medication and also experienced more side effects, especially at higher dosages. Thus, the use of lower dosages of niacin may be desirable in women. The results of this dose-escalation study show beneficial effects of Niaspan on the entire lipid profile. At the maximum recommended dosage of 2,000 mg/day, all lipid and lipoprotein levels changed in desirable directions. Side effects (other than flushing) and blood chemistries were comparable to those seen with immediate-release niacin.

Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.

Crystalline nicotinic acid (immediate-release niacin) is effective therapy for lipoprotein regulation and cardiovascular risk reduction. However, inconvenient regimens and unpleasant side effects decrease compliance. Sustained-release formulations designed to circumvent these difficulties increase hepatotoxicity. Niaspan, a new US Food and Drug Administration (FDA)-approved, once-daily, extended-release form, has been found effective and safe in short-term trials. The long-term efficacy and safety of Niaspan lipid monotherapy was studied in 517 patients (aged 21-75 years) for < or =96 weeks in dosages < or =3,000 mg/day. Primary efficacy endpoints were low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apo B) changes from baseline; secondary efficacy endpoints were changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, lipoprotein(a), and total cholesterol/HDL-cholesterol ratio; safety data included adverse events and laboratory values over the 2-year study period. LDL-cholesterol levels decreased significantly: 18% at week 48 and 20% at week 96; apo B reduction was similar (16% decrease at week 48 and 19% at week 96). Large elevations in HDL cholesterol (26%, week 48; 28%, week 96) allowed only modest decreases in total cholesterol (12% and 13%, respectively), whereas total cholesterol/HDL-cholesterol ratio decreased by almost one third. Triglyceride and lipoprotein(a) levels were decreased by 27% and 30%, respectively (week 48), and by 28% and 40%, respectively (week 96). All changes from baseline were significant (p <0.001). Niaspan was generally well tolerated, although flushing was common (75%); however, there was a progressive decrease in flushing with time from 3.3 episodes in the first month to < or = 1 episode by week 48. Aspirin was used by one third of patients before Niaspan dosing to minimize flushing episodes. Although serious adverse events occurred in about 10% of patients, none were considered probably or definitely related to Niaspan. Adverse events in general varied widely, but their true relation to the study drug is difficult to ascertain without a placebo (control) group. No deaths occurred. There were statistically significant changes in hepatic transaminases, alkaline phosphatase, direct bilirubin, phosphorus, glucose, amylase, and uric acid. However, these changes were mostly small and are not likely to be biologically or clinically significant (the decrease in phosphorus is a new finding in niacin therapy). No myopathy was observed. Thus, this long-term study confirms the earlier short-term findings that Niaspan is safe and effective as monotherapy in plasma lipoprotein regulation.

Effectiveness of once-nightly dosing of extended-release niacin alone and in combination for hypercholesterolemia.

We performed a multicenter, open-label study to determine the long-term safety and efficacy of a new extended-release once-a-night niacin preparation, Niaspan, in the treatment of hypercholesterolemia. Niaspan, 0.5 to 3.0 g once a night at bedtime, was used alone or in combination with a statin (inhibitor of hydroxymethylglutaryl coenzyme A reductase), a bile acid sequestrant, or both. Patients included 269 hypercholesterolemic male and female adults enrolled in a 96-week study, and 230 additional adults for whom short-term safety data were available. The dosages of Niaspan attained by 269 patients were 1,000 mg (95% of patients), 1,500 mg (86%), and 2,000 mg (65%). After 48 weeks of treatment, Niaspan alone (median dose 2,000 mg) reduced low-density lipaprotein (LDL) cholesterol (18%), apolipoprotein B (15%), total cholesterol (11%), triglycerides (24%), and lipoprotein(a) (36%), and increased high-density lipoprotein (HDL) cholesterol (29%). Niaspan plus a statin lowered LDL cholesterol (32%), apolipoprotein B (26%), total cholesterol (23%), triglycerides (30%), and lipoprotein(a) (19%), and increased HDL cholesterol (26%). Reversible elevations of aspartate aminotransferase or alanine aminotransferase more than twice the normal range occurred in 2.6% of patients. One patient discontinued Niaspan because of transaminase elevations. Intolerance to flushing, leading to discontinuation of Niaspan, occurred in 4.8% of patients. The overall rate of discontinuance due to flushing in this study combined with 2 previous randomized trials was 7.3%. In the long-term treatment of hypercholesterolemia, Niaspan produced favorable changes in LDL and HDL cholesterol, triglycerides, and lipoprotein(a). Adverse hepatic effects were minor and occurred at rates similar to those reported for statin therapy.

HLA class II antigens in rheumatic fever. Analysis of the DR locus by restriction fragment-length polymorphism and oligotyping.

We recently described an association of serologically defined HLA class II antigens DR7 and DR53 with RF. This study aimed at determining more precisely the class II gene associated with the disease. We studied patients and age- and race-matched controls. Genomic DNA was digested with four different enzymes and hybridized with HLA cDNA probes for DR beta, DQ beta, DQ alpha, and DP beta genes. RFLP analysis disclosed a fragment of 13,81 kb on Taq I DR beta blots, which correlates with HLA-DR53 and HLA-DR16, according to data from the Tenth International Histocompatibility Workshop. Of 24 patients, 20 (83.3%), were positive for the 13.81-kb/Taq I/DR beta allogenotope, compared with 16 (34%) of 47 healthy individuals (p = 0.000079, Fisher's exact test). Search for specific nucleotide sequences was performed using polymerase chain reaction technique. Oligonucleotides corresponding either to allele-specific DR7 and DR53 sequences, or shared by DRB1 and DRB3, DRB4, or DRB5 sequences were screened. Differences were tested throughout the second exon up to codon 100. Results were as expected by simple comparison with the published sequences of individual alleles. Although a clear association with DRB loci is shown, a susceptibility associated either with an allele or with a unique sequence was not found. A promiscuous presentation of the putative cross-reacting peptide or a heterogeneity of the causative agent might be the origin of these results. Genetic complementarity may be an additional factor defining inherited susceptibility to this disease.

Analysis of HLA haplotypes in autoimmune hepatitis type 1: identifying the major susceptibility locus.

Susceptibility to autoimmune hepatitis type I (AIH-1) has been associated with HLA-DR3, DR52, and DR4 antigens in Caucasian and Oriental patients. However, in Brazil, disease susceptibility is primarily linked to DR13 and DR52. In this highly admixed population, we find different DR13-associated haplotypes, presenting a unique opportunity to discriminate relevant genes within a tightly linked genomic region. To identify the primary susceptibility locus, we sequenced DR13 alleles of 39 patients with AIH-1 and 22 controls. Patients were almost exclusively DRB1*1301, but half of controls typed DRB1*1302. HLA-DQ haplotypes were varied. Oligotyping of DRB3 locus of all patients and also within the HLA-DR13 positive group showed an allele distribution comparable to controls, confirming that the stronger association lies in the DRB1 locus. On the other hand, if DRB1*1301 is the major susceptibility factor in our sample, the only amino acid different from DRB1*1302 in position 86, corresponding to pocket 1 in the peptide-presenting groove, may be important. We propose that peptide presentation leading to pathogenesis of AIH-1 may be quite stringent, but will also be affected by other strong genetic or environmental susceptibility factors, which would explain the various HLA molecules associated to the disease in the different populations.

HLA-DRB1*0405 is the predominant allele in Brazilian patients with Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada (VKH) disease is a rare disorder affecting pigmented structures especially the eye and is the main cause of autoimmune non-infectious uveitis in the Brazilian population. The autoimmune target is believed to be the melanocyte. A strong association of VKH disease with HLA-DR4 in the Japanese population is well known. The same association, albeit with lower relative risks has been found in other populations. A secondary association to HLA-DR1 involving a sequence linked with susceptibility to Rheumatoid Arthritis has also been described. VKH disease is more common in non-Caucasian populations. Brazilian patients of varying ethnic origins have been typed for HLA class II antigens. Several of the features found in other population samples are present. Over half of the patients typed HLA-DR4 (20/37) and typing with sequence-specific oligonucleotides disclosed predominance of the DRB1*0405 allele with a relative risk of 11.76 over the general population. In addition, HLA-DR1 and DQ4 were also present, in patients both positive and negative for HLA-DR4. These results suggest that, as in other autoimmune diseases, multiple overlapping susceptibility factors encoded by the MHC complex contribute to the overall susceptibility for the disease, the major factor however, being the presence of the DRB1*0405 allele.