Comparison of the efficacy and tolerability of topically administered azelastine,sodium cromoglycate and placebo in the treatment of seasonal allergic conjunctivitis and rhino-conjunctivitis

Objective and setting: Azelastine (AZE) in a novel, eye drop, formulation, was compared with topically applied sodium cromoglycate (SCG) and placebo (PLA) in the treatment of seasonal allergic conjunctivitis or rhino-conjunctivitis in a multicentre, parallel group study. Research design: 144 subjects ranging in age from 16 to 65 years participated. All had at least a 2-year history of seasonal allergic conjunctivitis and were symptomatic at the time of inclusion. Medications were administered topically either twice daily (AZE/PLA) or four times daily (SCG) over a 2-week treatment period. Method and outcome measures: Azelastine and placebo were compared double-blind; the comparison versus SCG was carried out in an open manner. Itching, redness, flow of tears, eyelid swelling, foreign-body sensation, photophobia, soreness and discharge were scored on a 4-point severity scale. RESULTS: Results for the decrease of main conjunctivitis symptoms (itching, tearing and conjunctival redness) showed a marked effect for both active treatments on day 3 with a sustained improvement on days 7 and 14. A clear response to treatment (an improvement of sum scores for day 3 of >/=3 points compared to baseline) occurred in 85.4% of azelastine-treated patients, 83.0% of sodium cromoglycate patients and 56.3% of placebo patients. Response rates for both active treatments were statistically superior to those for placebo (azelastine p = 0.005; sodium cromoglycate p = 0.007). Global assessment of efficacy was at least 'satisfactory' for 90.0% of azelastine patients, 81.3% of sodium cromoglycate patients and 66.3% of placebo-treated patients. The most frequent adverse effects were transient application site reactions which tended to disappear with increasing duration of treatment, and, less frequently, taste perversion. CONCLUSION: The results of this study indicate that the therapeutic use of azelastine eye drops in patients with seasonal allergic conjunctivitis or rhino-conjunctivitis can be recommended.     

Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo

Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (K(i) < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at approximately 100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes.     

Adverse drug events in trauma patients

BACKGROUND: Adverse drug events (ADEs) are noxious and unintended results of drug therapy. ADEs have been shown to be a risk to hospitalized patients. The purpose of this study was to determine the rate and nature of ADEs in trauma patients and to characterize the population at risk. METHODS: An electronic medical record, a hospital wide computerized surveillance program, and a clinical pharmacist prospectively investigated ADEs in 4,320 trauma patients from 1996 through 1999. RESULTS: The rate of ADEs in trauma patients (98/4320, 2.3%) was twice that of non-trauma hospital patients (1,111/96,218, 1.2%, p < 0.001). Traumatized females had ADEs 1.5 times more often than traumatized males (2.7% versus 1.8%, p = 0.052). The medication class most often associated with ADEs was analgesics with 54% involving morphine and 20% involving meperidine. The most common ADEs were nausea, vomiting, and itching. Only one ADE was directly attributed to a medical error. CONCLUSIONS: Trauma patients are at double the risk for ADEs. Analgesics are particularly associated with ADEs and use should be carefully monitored.     

Conventional measurements of GFR using <Superscript>51</Superscript>Cr-EDTA overestimate true renal clearance by 10 percent

It is widely believed that measurement of the area under the plasma clearance curve (AUC) following a single intravenous injection of chromium-51 labelled ethylene diamine tetra-acetic acid ((51)Cr-EDTA) is a gold standard method for determining glomerular filtration rate (GFR). However, there are reports that (51)Cr-EDTA may have a significant extrarenal clearance. The aim of this study was to identify the non-renal component of (51)Cr-EDTA plasma clearance contributing to the AUC measurement of GFR. Seventy healthy postmenopausal women (mean age 60 years, range 45-79 years) were injected with 3 MBq (51)Cr-EDTA and 0.25 MBq iodine-125 labelled human serum albumin and 11 blood samples taken between 0 and 4 h through an indwelling venous cannula. For the first 21 subjects, two complete urine collections were made 0-2 h and 2-4 h after injection, and for the final 49 patients, four 1-h urine collections were made. The mean (51)Cr-EDTA total plasma clearance was 84 ml/min (range 50-132 ml/min). The mean ratio (SEM) of urine to total clearance determined from the cumulative 1-, 2-, 3- and 4-h data was 0.903 (0.018), 0.891 (0.013), 0.898 (0.011) and 0.899 (0.010) respectively and remained constant despite the mean urine concentration decreasing from 122% to 15%/litre during this period. A least squares fit to data from the 238 individual urine collections was used to determine the fraction of the total plasma clearance attributable to renal clearance, alpha(0), and the residual urine volume, delta V. The results were alpha(0)=0.910 (95% CI: 0.889-0.932) and delta V=14 ml (95% CI: -4 to +34 ml). The overestimation of the true renal clearance of (51)Cr-EDTA by the AUC method is believed to be due to the failure of the plasma clearance curve to reach the true terminal exponential by 2 h after injection as usually assumed. As a result, conventional measurements of GFR using (51)Cr-EDTA overestimate the true renal clearance of tracer by approximately 10%.     

Effect of two breathing exercises (Buteyko and pranayama) in asthma: a randomised controlled trial

BACKGROUND: Patients with asthma are interested in the use of breathing exercises but their role is uncertain. The effects of the Buteyko breathing technique, a device which mimics pranayama (a yoga breathing technique), and a dummy pranayama device on bronchial responsiveness and symptoms were compared over 6 months in a parallel group study. METHODS: Ninety patients with asthma taking an inhaled corticosteroid were randomised after a 2 week run in period to Eucapnic Buteyko breathing, use of a Pink City Lung Exerciser (PCLE) to mimic pranayama, or a PCLE placebo device. Subjects practised the techniques at home twice daily for 6 months followed by an optional steroid reduction phase. Primary outcome measures were symptom scores and change in the dose of methacholine provoking a 20% fall in FEV(1) (PD(20)) during the first 6 months. RESULTS: Sixty nine patients (78%) completed the study. There was no significant difference in PD(20) between the three groups at 3 or 6 months. Symptoms remained relatively stable in the PCLE and placebo groups but were reduced in the Buteyko group. Median change in symptom scores at 6 months was 0 (interquartile range -1 to 1) in the placebo group, -1 (-2 to 0.75) in the PCLE group, and -3 (-4 to 0) in the Buteyko group (p=0.003 for difference between groups). Bronchodilator use was reduced in the Buteyko group by two puffs/day at 6 months; there was no change in the other two groups (p=0.005). No difference was seen between the groups in FEV(1), exacerbations, or ability to reduce inhaled corticosteroids. CONCLUSION: The Buteyko breathing technique can improve symptoms and reduce bronchodilator use but does not appear to change bronchial responsiveness or lung function in patients with asthma. No benefit was shown for the Pink City Lung Exerciser.     

Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor

The melanoma differentiation-associated gene 7 (mda-7), also called interleukin (IL)-24, suppresses the growth of some cancers in vitro and in vivo as a result of the ectopic expression of its protein. However, the function of the secreted form of the protein in cancer has not been previously studied. The purpose of this study was to determine the antiangiogenic function of a secreted form of the MDA-7/IL-24 protein (sMDA-7/IL-24). In vitro, sMDA-7/IL-24 inhibited both endothelial cell differentiation and migration of endothelial cells induced by vascular endothelial growth factor and basic fibroblast growth factor. The sMDA-7/IL-24-mediated inhibitory effect was 10-50 times more potent than endostatin, IFN-gamma, and IFN-inducible protein 10 in vitro. Furthermore, the inhibitory effect was not mediated by IFN or IFN-inducible protein 10. IL-22 receptor mediated the antiangiogenic activity of sMDA-7/IL-24. Administration of a blocking antibody to IL-22 receptor in conjunction with sMDA-7/IL-24 led to abrogation of inhibition of endothelial differentiation. sMDA-7/IL-24 inhibited vascular endothelial growth factor-induced angiogenesis as evidenced by reduced vascularization and hemoglobin content in in vivo Matrigel plug assays. In vivo, the growth of human lung tumor cells was significantly inhibited, and vascularization was reduced when the cells were mixed with 293 cells stably expressing sMDA-7/IL-24. Systemic administration of sMDA-7/IL-24 inhibited lung tumor growth in a mouse xenograft model. Associated with tumor growth inhibition was decreased tumor microvessel density and hemoglobin content, indicating the presence of antiangiogenic activity. These data demonstrate that sMDA-7/IL-24 is a novel and potent antiangiogenic effector and support the development of MDA-7/IL-24-based therapeutics.     

Senescing oral dysplasias are not immortalized by ectopic expression of hTERT alone without other molecular changes, such as loss of INK4A and/or retinoic acid receptor-beta: but p53 mutations are not necessarily required

Our previous work showed that acquisition of immortality at the dysplasia stage of oral cancer progression was consistently associated with four changes: loss of retinoic acid receptor (RAR)-beta and p16INK4A expression, p53 mutations and activation of telomerase. One atypical dysplasia (D17) that underwent delayed senescence after an extended lifespan showed loss of RAR-beta and p16INK4A/p14ARF expression, but retained functional wild-type p53 and telomerase was not activated. We now demonstrate that retroviral delivery of hTERT results in telomere lengthening and immortalization of D17 without loss of functional wild-type p53 activity. In contrast, the expression of hTERT in two other typical mortal dyplasia cultures (that retain RAR-beta and p16INK4A expression) does not extend their lifespan, even though telomeres are lengthened.