Efficacy and safety of biphasic insulin aspart 30 combined with pioglitazone in type 2 diabetes poorly controlled on glibenclamide (glyburide) monotherapy or combination therapy: an 18-week, randomized, open-label study

BACKGROUND: Few large randomized controlled trials have assessed the value of adding insulin to an oral antidiabetic drug regimen. OBJECTIVE: This trial compared the efficacy and safety of biphasic insulin aspart 30/70 (BIAsp 30) plus pioglitazone (n = 93), glibenclamide (glyburide) plus pioglitazone (n = 91), or BIAsp 30 monotherapy (n = 97). METHODS: This 18-week, multinational, multicenter, randomized, open-label, parallel-group trial involved 281 patients with type 2 diabetes (60% male; mean age, 56 years; mean body mass index, 29.5 kg/m2) with inadequate glycemic control (mean glycosylated hemoglobin [HbA(1c)], 9.5%; range, 7.4%-14.7%) on glibenclamide monotherapy or combination therapy. The primary objective was to compare end-of-trial HbA(1c) among the 3 treatment groups. Fasting and mean 7- and 8-point blood glucose profiles, blood lipid levels, plasminogen activator inhibitor levels, adverse events, and hypoglycemia frequency were also compared. Patients using BIAsp 30 (alone or with pioglitazone) were injected twice daily (immediately before breakfast and dinner). Pioglitazone (30 mg/d) and glibenclamide (5-15 mg/d) were taken orally once daily with or immediately after breakfast. RESULTS: At the end of the trial, HbA(1c) was significantly lower for the BIAsp 30 plus pioglitazone group than for the glibenclamide plus pioglitazone group (mean [SD], -0.64% [0.23%]; P = 0.005) and the BIAsp 30 monotherapy group (-0.60% [0.22%]; P = 0.008). Mean (SD) fasting blood glucose (before breakfast) was significantly lower for BIAsp 30 plus pioglitazone than for glibenclamide plus pioglitazone (153 [45] mg/dL vs 169 [65] mg/dL, respectively; P = 0.012). Each time point on the 8-point blood glucose profile was lower for BIAsp 30 plus pioglitazone than for glibenclamide plus pioglitazone (P < 0.001 to P < 0.05). No major hypoglycemic episodes were reported, and the absolute rate of hypoglycemic events was low (<1 event/patient-week) in the BIAsp-only group. Edema was reported in < or =9% of patients in each treatment group, but no occurrence was classified as serious. Weight gain (mean, 4.0 kg) was more common in the BIAsp plus pioglitazone group (8%); however, this was consistent with improved glycemic control and is similar to that reported in other pioglitazone trials. CONCLUSIONS: BIAsp 30 plus pioglitazone provided an efficacious and well-tolerated treatment alternative to glibenclamide plus pioglitazone or BIAsp 30 alone in this population of patients who previously were not well controlled on glibenclamide monotherapy or combination therapy.     

Anti-inflammatory effects of moxifloxacin on activated human monocytic cells: inhibition of NF-kappaB and mitogen-activated protein kinase activation and of synthesis of proinflammatory cytokines

We previously showed that moxifloxacin (MXF) exerts protective anti-inflammatory effects in immunosuppressed mice infected with Candida albicans by inhibiting interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) production in the lung. Immunohistochemistry demonstrated inhibition of nuclear factor (NF)-kappaB translocation in lung epithelium and macrophages in MXF-treated mice. In the present study we investigated the effects of MXF on the production of proinflammatory cytokines (i.e., IL-8, TNF-alpha, and IL-1beta) by activated human peripheral blood monocytes and THP-1 cells and analyzed the effects of the drug on the major signal transduction pathways associated with inflammation: NF-kappaB and the mitogen-activated protein kinases ERK and c-Jun N-terminal kinase (JNK). The levels of IL-8, TNF-alpha, and IL-1beta secretion rose 20- and 6.7-fold in lipopolysaccharide (LPS)-activated monocytes and THP-1 cells, respectively. MXF (5 to 20 microg/ml) significantly inhibited cytokine production by 14 to 80% and 15 to 73% in monocytes and THP-1 cells, respectively. In THP-1 cells, the level of NF-kappaB nuclear translocation increased fourfold following stimulation with LPS-phorbol myristate acetate (PMA), and this was inhibited (38%) by 10 microg of MXF per ml. We then assayed the degradation of inhibitor (I)-kappaB by Western blotting. LPS-PMA induced degradation of I-kappaB by 73%, while addition of MXF (5 microg/ml) inhibited I-kappaB degradation by 49%. Activation of ERK1/2 and the 46-kDa p-JNK protein was enhanced by LPS and LPS-PMA and was significantly inhibited by MXF (54 and 42%, respectively, with MXF at 10 microg/ml). We conclude that MXF suppresses the secretion of proinflammatory cytokines in human monocytes and THP-1 cells and that it exerts its anti-inflammatory effects in THP-1 cells by inhibiting NF-kappaB, ERK, and JNK activation. Its anti-inflammatory properties should be further assessed in clinical settings.     

Steroids for Migraine Headaches: A Randomized Double-Blind, Two-Armed, Placebo-Controlled Trial

Background: Recurrence of migraine headache after treatment in the emergency department (ED) is common. Conflicting evidence exists regarding the utility of steroids in preventing migraine headache recurrence at 24–48 h. Objective: To determine if steroids decrease the headache recurrence in patients treated for migraine headaches in the ED. Methods: Double-blind placebo-controlled, two-tailed randomized trial. Patients aged >17 years with a moderately severe migraine headache diagnosed by treating Emergency Physician were approached for participation. Enrollees received either dexamethasone (10 mg i.v.) if intravenous access was utilized or prednisone (40 mg by mouth × 2 days) if no intravenous access was obtained. Each medication was matched with an identical-appearing placebo. Patients were contacted 24–72 h after the ED visit to assess headache recurrence. Results: A total of 181 patients were enrolled. Eight were lost to follow-up, 6 in the dexamethasone group and 2 in the prednisone arm. Participants had a mean age of 37 years (±10 years), with 86% female. Eighty-six percent met the International Headache Society Criteria for migraine headache. Of the 173 patients with completed follow-up, 20/91 (22%) (95% confidence interval [CI] 13.5–30.5) in the steroid arm and 26/82 (32%) (95% CI 21.9–42.1) in the placebo arm had recurrent headaches (p = 0.21). Conclusion: We did not find a statistically significant decrease in headache recurrence in patients treated with steroids for migraine headaches.     

Smoking habits and obesity in young adults

AIMS: The aim of this work was to study the association between obesity and smoking habits in young adults. Specifically, we tested the hypothesis that obesity does not prevent young adults from smoking and conversely smoking does not protect against obesity. DESIGN AND SETTING: Trained nurses interviewed participants concerning demographic data and health behaviors such as smoking. At the time of the interview, weight and height were measured. Data were analyzed retrospectively. PARTICIPANTS: A representative sample of Israel Defense Force (IDF) personnel upon discharge from compulsory service, usually at the age of 20-21 years. FINDINGS: Overall, 29 745 participants were included during the 13-year study (16,363 males and 13,382 females). Smoking rates were higher among obese participants than among overweight and non-obese participants (34.9%, 37.1%, 43.6% for non-obese, overweight and obese, respectively; P < 0.001). Mean number of cigarettes smoked per day were also higher among smokers that were obese and overweight compared to the non-obese (15.2 +/- 9.2, 15.6 +/- 10.7, 18.0 +/- 9.8, respectively; P < 0.001). Overweight and obesity were associated with the father's lower academic educational level. In logistic regression analysis, obesity, year of study and parental academic education were correlated independently with smoking (P < 0.001). CONCLUSION: The positive association between obesity and smoking suggests that obesity is not a deterrent to smoking and also that smoking does not help to prevent obesity.     

Differences in the inflammatory response between patients with and those without diabetes mellitus after coronary stenting

Background: Patients with diabetes mellitus who undergo coronary stenting are at increased risk of restenosis. It is known that inflammation plays a crucial role in restenosis. Objective: We assessed the inflammatory response to elective coronary stent implantation (CSI) in stable diabetic and nondiabetic patients. Methods: C‐reactive protein (CRP), soluble (s) P‐selectin, and soluble intercellular adhesion molecule (sICAM)‐1 plasma levels were determined in diabetic (n = 51) and nondiabetic (n = 56) patients before and 48 hours and 4 weeks after bare metal stenting (BMS). Results: Diabetic patients presented significantly higher inflammatory marker levels before and after CSI. Nonetheless, diabetic and nondiabetic patients had postintervention peak of markers attained within 48 hours. At baseline, diabetic and nondiabetic patients presented CRP levels of 5.0 ± 20.1 (P ≤ 0.04) and 3.8 ± 9.4 μg/ml and, at 48 hours postintervention, 22.0 ± 20.2 (P = 0.001; P = 0.002) and 12.6 ± 11.3 (P ≤ 0.0001) μg/ml. Regarding sP‐selectin, diabetic and nondiabetic patients obtained levels of, at baseline, 182 ± 118 (P ≤ 0.04) and 105 ± 48 ng/ml and, at 48 hours, 455 ± 290 (P = 0.001; P ≤ 0.01) and 215 ± 120 (P ≤ 0.04) ng/ml. For diabetic and nondiabetic patients, sICAM‐1 levels were, at baseline, 248 ± 98 (P ≤ 0.04) and 199 ± 94 ng/ml and, at 48 hours, 601 ± 201 (P = 0.001; P ≤ 0.01) and 283 ± 220 (P = 0.001) ng/ml. At 4 weeks, for all patients, markers returned to preprocedural levels: versus before PCI: *P = 0.001, ^§P ≤ 0.0001; versus nondiabetic patients: ^#P ≤ 0.04, ^¶P = 0.002, ^?P ≤ 0.01. Conclusions: Diabetic and nondiabetic patients exhibited a temporal inflammatory response after an elective BMS. However, diabetic patients present higher preprocedural levels of CRP, sP‐selectin, and sICAM‐1 and reveal a further exacerbated inflammatory response after intervention. The differences in inflammatory response may have implications in restenosis within these two sets of patients.     

A randomized clinical trial to assess the efficacy of intramuscular droperidol for the treatment of acute migraine headache.

In a recent case series, we reported that intramuscular droperidol appeared to be an effective therapy for the treatment of acute migraine headache. The objective of the study was to further assess the efficacy of intramuscular droperidol for the treatment of acute migraine headache. The study design was a randomized, clinical trial set in a community-based ED. The population was a convenience sample of ED patients who met International Headache Society acute migraine criteria. Exclusions included pregnancy, use of narcotic or phenothiazine medications within 24 hours. For the protocol, patients were randomized to 1 of 2 treatment groups. Patients and physicians were blinded as to the treatment provided. Patients recorded their initial pain on a 100mm Visual Analog Scale (VAS) Patients were randomized to receive either 2.5 mg droperidol intramuscularly; the other group received 1.5 mg/kg meperidine intramuscularly. After 30 minutes patients recorded their pain on the VAS and recorded their preference for the medication on a Likert Scale. Physicians recorded the incidence of any side effects and the need for rescue medication. Statistical analysis consisted of categorical variables that were analyzed by chi-square, continuous interval data by t-tests and ordinal data by Mann-Whitney U test. The primary outcome parameters were mean VAS score change and the percentage of patients who wanted to go home without rescue medication. The study had an 80% power to detect a 26 mm difference in the mean change in VAS between groups. Of the 29 patients who were enrolled, 15 received droperidol. Both groups were similar with respect to age (30.7 +/- 8.9 years droperdol v 32.7 +/- 9.9 years meperidine; P =.59), female sex (73% v 71%; P =.91), mean headache duration (24.7 +/- 28.3 v 18.3 +/- 25.8 hours; P =.55). The droperidol group had a higher mean initial VAS score (88 v 76 mm; P =.03). The 2 groups were similar with regard to outcome, including: mean change in VAS score (47 v 37 mm; P =.33), average Likert score (1.1 v 1.9; P =.85), and the percentage of patients who did not want rescue medication (67% v 57%; P =.61). The incidence of sedation was 6.7 v 14.3%. Akathisia occurred in 13.3% of pts who received droperidol. We found that intramuscular droperidol was similar in efficacy to meperidine with a low incidence of side effects.     

Effect of flow on polymorphonuclear leukocyte/endothelial cell adhesion

The effect of flow on the adhesion of polymorphonuclear leukocytes (PMNL) to vascular endothelium was investigated using a parallel plate chamber with a well-defined flow field. Washed PMNL were perfused over a monolayer of primary human umbilical vein endothelial cells (HUVEC) pretreated with formyl-methionyl-leucyl-phenylalanine (FMLP, 1 X 10(-7) mol/L) for five minutes. In other experiments HUVEC were pretreated with interleukin 1 (IL1,2 U/mL) for four hours. PMNL adhesion to stimulated and control HUVEC was measured over a physiologic range of wall shear stresses. PMNL adhesion to nylon-coated surface was also studied. At a wall shear stress of 0.98 dynes/cm2,283 +/- 37.3 PMNL/mm2 (mean +/- SEM) adhered to FMLP-treated HUVEC while 195 +/- 20.3 PMNL/mm2 adhered to control HUVEC. At 1.96 dynes/cm2, 68 +/- 14.1 PMNL/mm2 adhered to FMLP-treated HUVEC and 42 +/- 6.0 PMNL/mm2 adhered to control HUVEC. At 3.92 dynes/cm2, virtually no PMNL adherence was noted on either control or FMLP-treated HUVEC. On IL 1-treated HUVEC at 1.96 dynes/cm2, 371 +/- 25.8 PMNL/mm2 adhered while 28 +/- 2.9 PMNL/mm2 adhered to control HUVEC. PMNL adhesion to IL 1-treated and control HUVEC dropped to 10.2 +/- 3.8 and 6.8 +/- 3.5 PMNL/mm2, respectively, at 3.01 dynes/cm2. The effect of flow on PMNL adhesion appears to be an important factor in determining the outcome of the PMNL/HUVEC adhesive interaction under these experimental conditions.     

Peptides modulating conformational changes in secreted chaperones: From in silico design to preclinical proof of concept

Blocking conformational changes in biologically active proteins holds therapeutic promise. Inspired by the susceptibility of viral entry to inhibition by synthetic peptides that block the formation of helix–helix interactions in viral envelope proteins, we developed a computational approach for predicting interacting helices. Using this approach, which combines correlated mutations analysis and Fourier transform, we designed peptides that target gp96 and clusterin, 2 secreted chaperones known to shift between inactive and active conformations. In human blood mononuclear cells, the gp96-derived peptide inhibited the production of TNFα, IL-1β, IL-6, and IL-8 induced by endotoxin by >80%. When injected into mice, the peptide reduced circulating levels of endotoxin-induced TNFα, IL-6, and IFNγ by >50%. The clusterin-derived peptide arrested proliferation of several neoplastic cell lines, and significantly enhanced the cytostatic activity of taxol in vitro and in a xenograft model of lung cancer. Also, the predicted mode of action of the active peptides was experimentally verified. Both peptides bound to their parent proteins, and their biological activity was abolished in the presence of the peptides corresponding to the counterpart helices. These data demonstrate a previously uncharacterized method for rational design of protein antagonists.     

Quality of life and patient-perceived difficulties in the treatment of type 2 diabetes

BACKGROUND: Clinical evidence points to patient-perceived difficulties and compliance problems in implementing early insulin therapy. Therefore, individual treatment aims are necessary to optimize diabetes therapy, as currently acknowledged by the new ADA/EASD guidelines. Better characterization of patient-perceived difficulties in the implementation of early insulin treatment may contribute to improved compliance and optimal tailoring of treatment regimens for the individual patient. OBJECTIVES: To assess differences in quality of life (QoL) and patient-perceived difficulties in health care with every addition of oral hypoglycemic agents (OHAs) and insulin therapy. METHODS: The analysis was conducted on a cross-sectional sample of 714 diabetic patients treated with OHAs or with insulin once or twice daily. Differences in diabetes-specific QoL, overall QoL, and perception of difficulties associated with specific diabetes treatment attributes were evaluated using trend analysis and comparisons between groups. The contribution of each diabetes treatment attribute to QoL measures and glycemic control was also assessed. RESULTS: No significant differences were found in QoL measures among patients treated exclusively with OHAs when these patients were assessed by the number of oral agents, irrespective of the degree of glycemic control. Better controlled patients treated with 2 OHAs, compared with poorly controlled patients treated with a single OHA, had a lower perception of difficulties associated with diabetes treatment attributes. Poorly controlled patients treated with 2 OHAs and better controlled patients treated with 3 OHAs had similar QoL and perceived difficulties with care. However, the insulin-based alternative was consistently associated with a significantly higher perception of pain and lower overall QoL when compared with the oral regimens. Multivariate models accounted for 52% and 32% of the variance in QoL measures. CONCLUSIONS: From the patients’ perspective, oral therapy is the preferred strategy for attaining the treatment goals since the addition of OHAs was not associated with lower QoL or patient-perceived difficulties with care. If early insulin treatment is considered, physicians should address specific diabetes treatment characteristics, mainly the issue of pain, to promote improved QoL and disease control.