Internists, Cardiologist (heart)
15 years of experience

Accepting new patients
University City
3400 Spruce St
Philadelphia, PA 19175
215-662-6779
Locations and availability (2)

Education ?

Medical School Score Rankings
Duke University (1995)
  • Currently 4 of 4 apples
Top 25%

Affiliations ?

Dr. Paolini is affiliated with 2 hospitals.

Hospital Affilations

Score

Rankings

  • Hospital of the University of PA
    Cardiology
    3400 Spruce St, Philadelphia, PA 19104
    • Currently 3 of 4 crosses
    Top 50%
  • Pennsylvania Hospital University PA Health System
    Cardiology
    800 Spruce St, Philadelphia, PA 19107
    • Currently 2 of 4 crosses
  • Publications & Research

    Dr. Paolini has contributed to 25 publications.
    Title Flushing Profile of Extended-release Niacin/laropiprant at Initiation of Therapy in Asian Lipid Clinic Patients.
    Date December 2009
    Journal Cardiology
    Excerpt

    Niacin is underutilized due to flushing, which occurs in over 90% of niacin-treated patients. Laropiprant (LRPT) reduces flushing associated with niacin. This study compared flushing with a combination tablet of extended-release (ER) niacin (ERN)/LRPT to niacin ER (N-ER; without LRPT) during the first week of therapy among patients in Asia.

    Title Flushing Profile of Extended-release Niacin/laropiprant Versus Gradually Titrated Niacin Extended-release in Patients with Dyslipidemia with and Without Ischemic Cardiovascular Disease.
    Date July 2009
    Journal The American Journal of Cardiology
    Excerpt

    Niacin has beneficial effects on a patient's lipid and lipoprotein profiles and cardiovascular risk, particularly at doses >2 g/day, but is underused due to flushing. Laropiprant (LRPT), a selective prostaglandin D(2) receptor-1 antagonist, decreases flushing associated with extended-release niacin (ERN). We compared flushing with ERN/LRPT dosed by a simplified 1-g --> 2-g regimen versus gradually titrated niacin extended-release (N-ER; given as NIASPAN, trademark of Kos Life Sciences LLC). Patients with dyslipidemia (n = 1,455) were randomized 1:1 to ERN/LRPT (1 g for 4 weeks advanced to 2 g for 12 weeks) or N-ER (0.5 g for 4 weeks titrated in 0.5-g increments every 4 weeks to 2 g for the final 4 weeks). Aspirin/nonsteroidal anti-inflammatory drugs were allowed to mitigate flushing. Flushing severity was assessed using the validated Global Flushing Severity Score (GFSS; none 0, mild 1 to 3, moderate 4 to 6, severe 7 to 9, extreme 10). Patients on ERN/LRPT, despite more rapid niacin titration, had less flushing than those on N-ER, as measured by number of days per week with moderate or greater GFSS across the treatment period (p <0.001). More than 2 times as many patients had no episodes of moderate, severe, or extreme flushing (GFSS > or =4) with ERN/LRPT than with N-ER (47.0% vs 22.0%, respectively) across the treatment period. Fewer patients on ERN/LRPT discontinued due to flushing than those on N-ER (7.4% vs 12.4%, p = 0.002). Other than the decrease in flushing, the safety and tolerability profile of ERN/LRPT was similar to that of N-ER. In conclusion, improvement in flushing with ERN/LRPT versus gradually titrated N-ER supports a rapidly advanced 1-g --> 2-g dosing regimen, allowing patients to start at 1 g and quickly reach and tolerate the optimal 2 g dose of ERN.

    Title Effects of Aspirin when Added to the Prostaglandin D2 Receptor Antagonist Laropiprant on Niacin-induced Flushing Symptoms.
    Date June 2009
    Journal Journal of Clinical Pharmacology
    Excerpt

    Niacin is an effective lipid-modifying therapy whose use has been limited by suboptimal tolerability. The adverse effect of flushing is due to prostaglandin D2 (PGD2)-mediated cutaneous vasodilation. Adjunctive treatment with the PGD2 receptor antagonist laropiprant significantly reduces the incidence and severity of niacin-induced flushing. The objective of this study was to assess the effect of aspirin pretreatment on flushing symptoms with extended-release (ER) niacin/laropiprant in healthy volunteers. A randomized, double-blind, placebo-controlled crossover study compared patient-rated flushing following pretreatment with aspirin 325 mg versus placebo administered 30 minutes before ER niacin 2 g/laropiprant 40 mg. Flushing responses were assessed using participant-reported overall symptom severity score (OSSS), including individual characteristics of redness, warmth, tingling, or itching. The overall incidence and severity of flushing were comparable for participants receiving aspirin or placebo before ER niacin 2 g/laropiprant 40 mg. The difference in 3-day average OSSS between treatments was 0.2 (P=.180). Profiles of flushing severity, frequency, and bothersomeness were comparable for the aspirin/ER niacin/laropiprant and ER niacin/laropiprant regimens. All treatments were safe and well tolerated. Coadministration of aspirin 325 mg daily with ER niacin 2 g/laropiprant 40 mg does not further reduce residual flushing symptoms associated with ER niacin 2 g/laropiprant 40 mg alone.

    Title Lipid-modifying Efficacy and Tolerability of Extended-release Niacin/laropiprant in Patients with Primary Hypercholesterolaemia or Mixed Dyslipidaemia.
    Date April 2009
    Journal International Journal of Clinical Practice
    Excerpt

    Improving lipids beyond low-density lipoprotein cholesterol (LDL-C) lowering with statin monotherapy may further reduce cardiovascular risk. Niacin has complementary lipid-modifying efficacy to statins and cardiovascular benefit, but is underutilised because of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that reduces niacin-induced flushing has been combined with extended-release niacin (ERN) into a fixed-dose tablet.

    Title A Comparison of the Pharmacokinetics of Two Different Formulations of Extended-release Niacin.
    Date April 2009
    Journal Current Medical Research and Opinion
    Excerpt

    The objective of this study was to compare pharmacokinetic parameters of niacin extended-release tablets (NER uncoated) and niacin extended-release caplet formation (NER coated).

    Title Blood Pressure-lowering Effects of Extended-release Niacin Alone and Extended-release Niacin/laropiprant Combination: a Post Hoc Analysis of a 24-week, Placebo-controlled Trial in Dyslipidemic Patients.
    Date April 2009
    Journal Clinical Therapeutics
    Excerpt

    Dyslipidemia and high blood pressure are both major cardiovascular disease risk factors. Niacin is an effective lipid-altering agent that has been reported to reduce the risk of cardiovascular disease. However, the more widespread use of niacin is limited, mainly due to the occurrence of flushing. Laropiprant (LRPT) is a selective antagonist of prostaglandin D(2) receptor subtype 1 that reduces extended-release niacin (ERN)-induced flushing without affecting its beneficial lipid effects. While the lipid effects of ERN are well known, the blood pressure effects are unclear.

    Title Effects of Laropiprant on Nicotinic Acid-induced Flushing in Patients with Dyslipidemia.
    Date April 2008
    Journal The American Journal of Cardiology
    Excerpt

    Niacin (nicotinic acid) is not optimally used mainly because of flushing, a process mediated primarily by prostaglandin D(2), which leads to poor patient compliance and suboptimal dosing. This phase II dose-ranging study was designed to assess whether the prostaglandin D(2) receptor 1 antagonist laropiprant (LRPT; MK-0524) would (1) reduce extended-release niacin (ERN)-induced flushing in dyslipidemic patients and (2) support a novel accelerated ERN dosing paradigm: initiating ERN at 1 g and advancing rapidly to 2 g. In part A of the study, 154 dyslipidemic patients were randomized to LRPT 150 mg/day or placebo in a 9-week, 2-period crossover study. Patients who completed part A (n = 122) entered part B (after a 2-week washout), together with additional patients who entered part B directly (n = 290). Part B patients were randomized to placebo, ERN 1 g (Niaspan, no previous titration), or ERN 1 g coadministered with LRPT 18.75, 37.5, 75, or 150 mg for 4 weeks, with doubling of the respective doses for the remaining 4 weeks. Patients treated with LRPT plus ERN experienced significantly less ERN-induced flushing than those treated with ERN alone during the initiation of treatment (ERN 1 g, week 1) and the maintenance treatment (ERN 1 to 2 g, weeks 2 to 8). All doses of LRPT were maximally effective in inhibiting niacin-induced flushing. LRPT did not alter the beneficial lipid effects of ERN. LRPT plus ERN was well tolerated. In conclusion, the significant reduction in ERN-induced flushing provided by LRPT plus ERN supports an accelerated ERN dose-advancement paradigm to achieve rapidly a 2-g dose in dyslipidemic patients.

    Title Validation of a Questionnaire to Assess Niacin-induced Cutaneous Flushing.
    Date September 2007
    Journal Current Medical Research and Opinion
    Excerpt

    BACKGROUND: Niacin is currently the most effective approved agent for raising high-density lipoprotein cholesterol. However, niacin-induced cutaneous flushing (redness, warmth, tingling and/or itching) significantly limits patient acceptance. To further characterize flushing, a patient-reported Flushing Symptom Questionnaire (FSQ) was developed and validated. METHODS: The FSQ was validated in an 8-week, randomized, double-blind, placebo-controlled trial of extended-release (ER) niacin and placebo. The primary flushing endpoint of the study was based on the single Global Flushing Severity Score (GFSS), an item within the FSQ, which assesses overall flushing severity on a 0-10 discretized analog scale. RESULTS: A total of 175 patients were randomized to one of four treatment groups (sequences of placebo and ER niacin [given as niacin (NIASPAN) 1 g (N1) and 2g (N2)]. Test-retest reliability and reproducibility coefficients for the single-item GFSS were all above 0.75. Construct validity was supported by moderate to strong correlations (r > 0.5) with other FSQ items. All FSQ item scores and specifically the GFSS discriminated between treatment groups and demonstrated expected relationships with predefined known groups. The GFSS demonstrated high responsiveness in patients who switched from ER niacin to placebo. The ability of the GFSS and GFBS to discriminate changes in flushing symptoms in patients who increased drug dose was less than expected possibly due to accommodation to the flushing effects of niacin over time; differential drop-out due to flushing; and/or FSQ items not being sensitive enough to detect a change that was present. CONCLUSIONS: The FSQ items and specifically the Global Flushing Severity Score (GFSS), are reliable and valid measures to assess niacin-induced flushing.

    Title Effects of Ezetimibe on Cyclosporine Pharmacokinetics in Healthy Subjects.
    Date July 2006
    Journal Journal of Clinical Pharmacology
    Excerpt

    This single-center, open-label, 2-period crossover study investigated the effects of multiple-dose ezetimibe (EZE) on a single dose of cyclosporine (CyA). Healthy subjects received 2 treatments in random order with a 14-day washout: (1) CyA 100 mg alone and (2) EZE 20 mg for 7 days with CyA 100 mg coadministered on day 7; EZE 20 mg alone was administered on day 8. AUC(0-last) and Cmax geometric mean ratios (90% confidence interval) for ([CyA + EZE]/CyA alone) were 1.15 (1.07, 1.25) and 1.10 (0.97, 1.26), respectively. Tmax (approximately 1.3 hours) was similar with and without EZE (P >.200). Mean CyA exposure slightly increased (approximately 15%) with multiple-dose EZE 20 mg; however, this value was contained within (0.80, 1.25). The implications for chronic EZE dosing within the usual clinical paradigm of chronic CyA dosing have not been established; caution is recommended when using these agents concomitantly. CyA concentrations should be monitored in patients receiving EZE and CyA.

    Title Interaction of Single-dose Ezetimibe and Steady-state Cyclosporine in Renal Transplant Patients.
    Date July 2006
    Journal Journal of Clinical Pharmacology
    Excerpt

    This open-label, single-period study evaluated the single-dose pharmacokinetics of ezetimibe (EZE) 10 mg in the setting of steady-state cyclosporine (CyA) dosing in renal transplant patients. A single 10-mg dose of EZE was coadministered with the morning dose of CyA (75-150 mg twice a day). Total EZE (sum of unconjugated, parent EZE and EZE-glucuronide; EZE-total) AUC(0-last) and Cmax were compared to values derived from a prespecified database of healthy volunteers. Geometric mean ratios (90% CIs) for (EZE + CyA)/EZE alone for EZE-total AUC((0-last)) and Cmax were 3.41 (2.55, 4.56) and 3.91 (3.13, 4.89), respectively. Compared to healthy controls, EZE-total AUC((0-last)) was 3.4-fold higher in transplant patients receiving CyA; similar exposure levels were seen in a prior multiple-dose study in which EZE 50 mg was administered to healthy volunteers without dose-related toxicity. Because the long-term safety implications of both higher EZE exposures and undetermined effect on CyA are not yet understood, the clinical significance of this interaction is unknown.

    Title Bioequivalence of an Ezetimibe/simvastatin Combination Tablet and Coadministration of Ezetimibe and Simvastatin As Separate Tablets in Healthy Subjects.
    Date April 2006
    Journal International Journal of Clinical Pharmacology and Therapeutics
    Excerpt

    OBJECTIVE: To assess the bioequivalence of an ezetimibe/simvastatin (EZE/SIMVA) combination tablet compared to the coadministration of ezetimibe and simvastatin as separate tablets (EZE + SIMVA). METHODS: In this open-label, randomized, 2-part, 2-period crossover study, 96 healthy subjects were randomly assigned to participate in each part of the study (Part I or II), with each part consisting of 2 single-dose treatment periods separated by a 14-day washout. Part I consisted of Treatments A (EZE 10 mg + SIMVA 10 mg) and B (EZE/SIMVA 10/10 mg/mg) and Part II consisted of Treatments C (EZE 10 mg + SIMVA 80 mg) and D (EZE/SIMVA 10/80 mg/mg). Blood samples were collected up to 96 hours post-dose for determination of ezetimibe, total ezetimibe (ezetimibe + ezetimibe glucuronide), simvastatin and simvastatin acid (the most prevalent active metabolite of simvastatin) concentrations. Ezetimibe and simvastatin acid AUC(0-last) were predefined as primary endpoints and ezetimibe and simvastatin acid Cmax were secondary endpoints. Bioequivalence was achieved if 90% confidence intervals (CI) for the geometric mean ratios (GMR) (single tablet/coadministration) of AUC(0-last) and Cmax fell within prespecified bounds of (0.80, 1.25). RESULTS: The GMRs of the AUC(0-last) and Cmax for ezetimibe and simvastatin acid fell within the bioequivalence limits (0.80, 1.25). EZE/ SIMVA and EZE + SIMVA were generally well tolerated. CONCLUSIONS: The lowest and highest dosage strengths of EZE/SIMVA tablet were bioequivalent to the individual drug components administered together. Given the exact weight multiples of the EZE/SIMVA tablet and linear pharmacokinetics of simvastatin across the marketed dose range, bioequivalence of the intermediate tablet strengths (EZE/SIMVA 10/20 mg/mg and EZE/SIMVA 10/40 mg/mg) was inferred, although these dosages were not tested directly. These results indicate that the safety and efficacy profile of EZE + SIMVA coadministration therapy can be applied to treatment with the EZE/SIMVA tablet across the clinical dose range.

    Title Ezetimibe: a Review of Its Metabolism, Pharmacokinetics and Drug Interactions.
    Date August 2005
    Journal Clinical Pharmacokinetics
    Excerpt

    Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active ezetimibe-glucuronide. Total ezetimibe (sum of 'parent' ezetimibe plus ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of ezetimibe and ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5'-diphosphate-glucuronosyltransferase isoenzymes to form ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as ezetimibe, with the balance found in the urine mainly as ezetimibe-glucuronide. Overall, ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total ezetimibe). Hence, ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of ezetimibe. Finally, higher ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.

    Title Simvastatin Does Not Have a Clinically Significant Pharmacokinetic Interaction with Fenofibrate in Humans.
    Date December 2004
    Journal Journal of Clinical Pharmacology
    Excerpt

    Simvastatin and fenofibrate are both commonly used lipid-regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2-period, randomized, open-label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80-mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160-mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160-mg micronized fenofibrate capsule dosed together with an 80-mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady-state pharmacokinetics (AUC(0-24h), C(max), and t(max)) of active and total HMG-CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady-state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC(0-24h) (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG-CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC(0-24h) and C(max) were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated.

    Title Leukocyte Recruitment and Expression of Chemokines Following Different Forms of Vascular Injury.
    Date December 2003
    Journal Vascular Medicine (london, England)
    Excerpt

    Inflammation plays a central role in restenosis following coronary intervention. Recent human and animal data suggest important differences between the inflammatory responses to simple balloon angioplasty compared with stent implantation. To investigate the mechanisms of these differences, New Zealand white rabbits underwent bilateral iliac artery balloon denudation. Half received intravascular stents. Arteries were harvested at three, seven and 14 days for immunohistochemistry, and 4 hours, 8 hours and 14 days for chemokine mRNA analysis. Leukocyte content was quantified utilizing immunohistochemistry (RPN357, monoclonal antibody (mAb) against rabbit neutrophil; RAM-11, mAb against rabbit macrophage). We analyzed the mRNA levels of the chemokines monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8) through semi-quantitative polymerase chain reaction. We demonstrated the spatial pattern of MCP-1 mRNA levels through in situ mRNA hybridization. In balloon-injured arteries, leukocyte recruitment was confined to early neutrophil infiltration. IL-8 and MCP-1 mRNA levels peaked within hours and were undetectable at 14 days. In contrast, in stented arteries, early neutrophil recruitment was followed by prolonged macrophage accumulation. IL-8 and MCP-1 mRNA levels peaked within hours but were still detectable 14 days post injury. Conclusions: In contrast to balloon injury, stent-induced injury results in sustained chemokine expression and leukocyte recruitment. These data may have important implications for antirestenotic strategies.

    Title The Chemokines Il-8, Monocyte Chemoattractant Protein-1, and I-309 Are Monomers at Physiologically Relevant Concentrations.
    Date October 1994
    Journal Journal of Immunology (baltimore, Md. : 1950)
    Excerpt

    The chemokines are a family of immune mediators involved in a wide range of inflammatory processes, most importantly as chemoattractants of monocytes, neutrophils, lymphocytes, and fibroblasts to sites of inflammation. Nuclear magnetic resonance and x-ray crystallographic studies have shown that IL-8 and macrophage-inflammatory protein-1 beta (MIP-1 beta) form noncovalent dimers and that platelet factor-4 (PF-4) forms noncovalent dimers and tetramers, leading to the assumption that, as a family, the chemokines would form multimeric structures. In this study, we analyze the association states of the chemokines IL-8, monocyte chemoattractant protein-1 (MCP-1), and I-309, by using a combination of size exclusion HPLC, sedimentation equilibrium ultracentrifugation, and chemical cross-linking. We find that the association states of MCP-1 and IL-8 are characterized by an equilibrium between monomers and dimers: although dimers predominate at concentrations above 100 microM, these chemokines are almost exclusively monomeric at the nanomolar concentrations at which they display maximal chemotactic activity. I-309, by contrast, remains a monomer at all concentrations tested. I-309 contains two additional cysteine residues (C26 and C68) that are not found in any other members of the chemokine family. We used cyanogen bromide and trypsin digestion strategies to demonstrate that these two residues are linked in a unique intramolecular disulfide bond. Furthermore, by using site-directed mutagenesis, we show that the integrity of this bond is crucial for protein secretion.

    Title Cardiac Ejection Fraction: Phantom Study Comparing Cine Mr Imaging, Radionuclide Blood Pool Imaging, and Ventriculography.
    Date May 1992
    Journal Journal of Magnetic Resonance Imaging : Jmri
    Excerpt

    The accuracy and reproducibility of cardiac ejection fraction (EF) measurements based on cine magnetic resonance (MR) imaging, radionuclide multigated acquisition (MUGA) blood pool imaging, and angiographic ventriculography were evaluated by comparing them with a volumetrically determined standard. A biventricular, compliant, fluid-filled heart phantom was developed to mimic normal cardiac anatomy and physiology. Ventricular EFs were measured with cine MR imaging by summation of nine contiguous 10-mm-thick sections in short and long axis, with single-plane ventriculography, and with MUGA. Three measurements were performed with each modality for each of three EFs. Ventriculography was least accurate, with average relative errors ranging from 7.9% for the largest EF to 60.1% for the smallest. Cine MR was most accurate, with average relative errors ranging from 4.4% to 8.5%. MUGA EF measurements showed good correlation, with average relative errors ranging from 7.1% to 22.4%. Comparison of the error variances for the three modalities with the F test revealed that MR and MUGA EF measurements were significantly more accurate than those based on ventriculography (P less than .01). No significant difference was demonstrated between the accuracy of short- and long-axis cine MR acquisitions.

    Title Characterization of a Novel Human Corneal Endothelial Antigen.
    Date September 1991
    Journal Investigative Ophthalmology & Visual Science
    Excerpt

    The antigenic composition of the human corneal endothelium, a cellular layer essential for maintaining corneal function, has not been well characterized. A novel corneal endothelial antigen was identified by generating a monoclonal antibody (MAb) against normal human corneal endothelial cells. This MAb, designated 2B4.14.1, reacted strongly by immunoperoxidase staining with the endothelium of corneas from all human donors tested but not with other corneal components, including epithelium and stroma. Positive immunohistologic reactions of 2B4.14.1 with several other human tissues, including kidney (parietal epithelium of Bowman's capsule, proximal convoluted tubule, ascending limb of Henle's loop, and distal convoluted tubule), glandular epithelia of numerous organs, and mesothelial linings of several thoracic and abdominal viscera, also were observed. One of the renal antigens recognized by 2B4.14.1 was identified as Tamm-Horsfall glycoprotein (THGP), based on the ability of the antibody to recognize THGP in western immunoblots and the abrogation of immunohistologic reactivity of the antibody by preincubation with purified THGP. These findings raise the possibility that the human cornea expresses a molecule with homeostatic properties similar to those ascribed to THGP. However, it is unlikely that the corneal antigen recognized by 2B4.14.1 is conventional THGP; a MAb specific for THGP did not react with corneal endothelium.

    Title Measuring Flushing Symptoms with Extended-release Niacin Using the Flushing Symptom Questionnaire: Results from a Randomised Placebo-controlled Clinical Trial.
    Date
    Journal International Journal of Clinical Practice
    Excerpt

    Introduction: Niacin is underutilised because of flushing. Lack of a quantitative tool to assess niacin-induced flushing has precluded the objective evaluation of flushing associated with extended-release (ER) niacin formulations. We developed the Flushing Symptom Questionnaire((c)) (FSQ), a quantitative tool to assess patient-reported flushing, and assessed its ability to characterise ER niacin-induced flushing. Methods: This study focused on the responses to one question in the FSQ, the Global Flushing Severity Score (GFSS), reported on a 0-10 scale (none = 0, mild = 1-3, moderate = 4-6, severe = 7-9 and extreme = 10) to assess flushing during ER niacin initiation (week 1) and maintenance (weeks 2-8). Results: Flushing severity with ER niacin was greatest during week 1 and remained greater than placebo for the study duration. During weeks 2-8, 40% of patients on ER niacin vs. 8% of those on placebo had > 1 day/week with 'moderate or greater' GFSS. Conclusions: In conclusion, the GFSS component of the FSQ was a sensitive and responsive quantitative measure of ER niacin-induced flushing that will aid in the objective comparison of novel strategies intended to improve tolerability and adherence to niacin, an agent proven to reduce cardiovascular risk.

    Title Extended-release Niacin/laropiprant: Reducing Niacin-induced Flushing to Better Realize the Benefit of Niacin in Improving Cardiovascular Risk Factors.
    Date
    Journal Cardiology Clinics
    Excerpt

    Treatment with niacin effectively improves multiple lipid parameters and cardiovascular outcomes. Widespread use of niacin, however, is limited by flushing, which is mediated primarily by prostaglandin D2 (PGD2). Laropiprant is a selective PGD2 receptor 1 (DP1) antagonist that reduces objective measures of niacin-induced flushing symptoms upon initiation of therapy and with more chronic use. Results from early dosing and formulation studies have culminated in the development of a combination extended-release (ER) niacin/laropiprant tablet aimed at providing the beneficial lipid-modifying effects of niacin, while reducing niacin-induced flushing. The improvement in the tolerability of niacin with ER niacin/laropiprant allows niacin dosing to initiate directly at 1 g and rapidly advance to a 2-g target dose. ER niacin/laropiprant generally is tolerated well and represents a new treatment option for dyslipidemia that offers the potential for more patients to receive the lipid-modifying and cardiovascular benefits of niacin.

    Title Ongoing Tirofiban in Myocardial Infarction Evaluation (on-time) 2 Trial: Rationale and Study Design.
    Date
    Journal Eurointervention : Journal of Europcr in Collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology
    Excerpt

    Aims: Delays in initiation of treatment because of transportation of high-risk patients with ST-elevation myocardial infarction (STEMI) are associated with worse clinical outcome. Glycoprotein IIb/IIIa receptor inhibitors improve initial patency of the infarct-related vessel and reduce thrombotic complications in patients undergoing percutaneous coronary intervention (PCI).Methods and results: The Ongoing Tirofiban In Myocardial infarction Evaluation (On-TIME) 2 trial is a randomised, double-blind, European clinical trial to evaluate the benefits of pre-hospital initiation of high-dose bolus of tirofiban, a glycoprotein IIb/IIIa receptor inhibitor, on background therapy of aspirin, unfractionated heparin and high dose clopidogrel, for patients with STEMI who undergo primary PCI. Eligible patients will be randomised 1:1 to pretreatment with a 25 microg/kg bolus and 0.15 microg/kg/min maintenance infusion of tirofiban or placebo. The primary endpoint is the extent of residual ST-segment deviation (defined as percentage of patients with >3 mm deviation of ST segment) 1 hour after PCI. The key secondary endpoint is the combined occurrence of death, recurrent myocardial infarction, urgent target vessel revascularisation, or thrombotic bailout at 30 days. The trial will continue until 958 patients are randomly assigned to treatment.Conclusions: The On-TIME 2 trial evaluates whether pre-hospital initiation of high-dose bolus tirofiban is effective for patients with STEMI who are candidates to undergo PCI. This placebo-controlled trial will provide important evidence regarding the benefit of initiating a GP IIb/IIIa inhibitor, in combination with high-dose clopidogrel and unfractionated heparin.

    Title Efficacy and Safety of Extended-release Niacin/laropiprant Plus Statin Vs. Doubling the Dose of Statin in Patients with Primary Hypercholesterolaemia or Mixed Dyslipidaemia.
    Date
    Journal International Journal of Clinical Practice
    Excerpt

    Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction. However, niacin is underutilised because of the side effects of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). A combination tablet containing extended-release niacin and laropiprant (ERN/LRPT), a PGD(2) receptor (DP1) antagonist, offers improved tolerability. This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal based on their coronary heart disease risk category (high, moderate or low).

    Title Safety of Extended-release Niacin/laropiprant in Patients with Dyslipidemia.
    Date
    Journal Journal of Clinical Lipidology
    Excerpt

    To evaluate the safety profile of extended-release niacin/laropiprant (ERN/LRPT), pooling data from studies in the clinical development program.

    Title Efficacy and Tolerability of Extended-release Niacin/laropiprant in Dyslipidemic Patients with Metabolic Syndrome.
    Date
    Journal Journal of Clinical Lipidology
    Excerpt

    Patients with metabolic syndrome (MetS) are at increased risk for cardiovascular disease. Niacin improves lipid abnormalities associated with MetS, but is underused, mainly because of flushing. Laropiprant (LRPT) reduces niacin-induced flushing and, in combination with extended-release niacin (ERN/LRPT), improves lipid levels.

    Title Effects of a Niacin Receptor Partial Agonist, Mk-0354, on Plasma Free Fatty Acids, Lipids, and Cutaneous Flushing in Humans.
    Date
    Journal Journal of Clinical Lipidology
    Excerpt

    Development of niacin-like agents that favorably affect lipids with an improved flushing profile would be beneficial.

    Title Lipid-modifying Efficacy of Extended Release Niacin/laropiprant in Asian Patients with Primary Hypercholesterolemia or Mixed Hyperlipidemia.
    Date
    Journal Journal of Clinical Lipidology
    Excerpt

    Niacin has proven lipid-modifying efficacy and cardiovascular benefit; however, it is underused because of skin flushing, a process mediated primarily by prostaglandin D(2) (PGD(2)). Laropiprant (LRPT), a PGD(2) receptor (DP1) antagonist that mitigates niacin-induced flushing, has been combined with extended-release niacin (ERN) into a fixed-dose tablet containing 1g of ERN and 20mg of LRPT (ERN/LRPT 1g). In a large-scale (n=∼1600), multinational, 6-month study in dyslipidemic patients, ERN/LRPT 2g produced superior lipid-modifying efficacy vs placebo, whether administered alone or with concomitant statins.


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