Randomized efficacy and safety trial of once-daily remogliflozin etabonate for the treatment of type 2 diabetes.

The sodium-dependent glucose transporter 2 (SGLT2) inhibitor remogliflozin etabonate (RE) was evaluated in a 12-week, double-blind, randomized, placebo- and active-controlled, parallel-group study. A total of 252 newly diagnosed and drug-naïve people with type 2 diabetes and glycated haemoglobin (HbA1c) concentrations of 7.0-≤9.5% (53-80 mmol/mol) were recruited. Participants were randomized to RE (100, 250, 500 or 1000 mg once daily or 250 mg twice daily), placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c concentration from baseline. Secondary endpoints included changes in fasting plasma glucose, body weight and lipid profiles, safety and tolerability. We observed a statistically significant trend in the RE dose-response relationship for change from baseline in HbA1c at week 12 (p < 0.047). RE was generally well tolerated and no effects on LDL cholesterol were observed.

Randomized trial showing efficacy and safety of twice-daily remogliflozin etabonate for the treatment of type 2 diabetes.

We compared the efficacy of twice-daily doses of remogliflozin etabonate (RE) and once-daily pioglitazone with placebo for reduction in glycated haemoglobin (HbA1c) concentration. In this 12-week, double-blind, randomized, active- and placebo-controlled trial, 336 treatment-naïve subjects with type 2 diabetes and an HbA1c of 7.0-9.5% (53-80 mmol/mol) were randomized to RE (50, 100, 250, 500 or 1000 mg twice daily), matching placebo or 30 mg pioglitazone once daily. The primary endpoint was change in HbA1c from baseline. Other endpoints included changes in body weight, lipid levels, safety and tolerability. RE produced a decreasing dose response in HbA1c at week 12 (p < 0.001), with reductions in HbA1c versus placebo ranging from 0.64 to 1.07% (p < 0.001). Statistically significant reductions in body weight for RE compared with placebo were also observed. Twice-daily RE resulted in a dose-ordered improvement in glycaemic control and was generally well tolerated.

An investigation into the effect and mechanisms of action of nicotine in inflammatory bowel disease.

OBJECTIVE AND DESIGN: To determine the effect of nicotine on colonic inflammation in the trinitrobenzenesulphonic acid (TNBS) model of inflammatory bowel disease in comparison with sulphasalazine. MATERIALS: Male Wistar rats were used for the in-vivo and ex-vivo studies. In-vitro studies were performed using human leukemia peripheral blood monocyte cells (THP-1 cells) grown in continuous culture. TREATMENT: Rats were given access to either nicotine (5 or 100 microg/mL) or sulphasalazine (375 microg/mL) in their drinking water for 10 or 2 days respectively before and 3 days after TNBS administration. THP-1 cells were treated with nicotine (10(-14) to 10(-11) M) for 2 h before and after stimulation with 3 microg/mL lipopolysaccharide (LPS). METHODS: Inflammation in the TNBS model was assessed by measuring the tissue myeloperoxidase activity, leukotriene B4 concentration, inducible nitric oxide protein expression, the ex-vivo production of tumour necrosis factor alpha (TNFalpha), macroscopic damage score, plasma corticosterone levels and by a qualitative histological evolution. The effect of nicotine on TNFalpha production in LPS stimulated THP-1 monocyte cells in-vitro was also determined. Statistical comparisons were made using the Mann-Whitney U-test for the macroscopic damage score and an ANOVA for all other parameters. RESULTS: TNBS treated rats given access to 100 microg/mL nicotine in their drinking water had a marked reduction in several of the markers of inflammation compared to control TNBS treated rats, but a greater reduction was found at 5 microg/mL nicotine or 375 microg/mL sulphasalazine, the latter producing comparable reductions in inflammation to the low dose nicotine. Nicotine also caused a significant reduction in TNFalpha release from THP-1 cells. CONCLUSIONS: Nicotine reduced inflammation in the TNBS model of colonic damage confirming the use of nicotine in IBD although the choice of dose requires further investigation. The mechanism of action of nicotine does not involve increased corticosterone levels, but may be a consequence of a reduction in TNFalpha or leukotriene B4 production.

Equivalence of as-required salbutamol propelled by propellants 11 and 12 or HFA 134a in mild to moderate asthmatics. German Study Group.

This randomized, double-blind, parallel-group study compared the efficacy and tolerability of as-required salbutamol 100 microg administered from either a chlorofluorocarbon (CFC) pressurized metered dose inhaler (pMDI; Ventolin) or from a non-CFC hydrofluoroalkane (HFA) 134a pMDI (Ventolin CFC-free) in patients with mild to moderate asthma. All patients (n = 423) continued with their standard asthma therapy, and recorded their daily use of study medication, morning and evening peak expiratory flow (PEF) and symptom scores, throughout the 4-week treatment period. Clinic lung function was measured at 2-week intervals. The median daily use of inhaled study medication remained constant at four actuations per day throughout the study in both treatment groups and statistical analysis indicated that the two formulations were equivalent. Small improvements in both treatment groups were reported in mean morning and evening PEF, clinic forced expiratory volume in 1 sec and clinic PEF and there were no significant differences between the two groups. Both formulations were well tolerated. This study indicates that as-required salbutamol 100 microg administered via a HFA 134a pMDI is as effective and safe as the currently available CFC-propelled formulation.

Equivalence of salbutamol 200 microg four times daily propelled by propellants 11 and 12 or HFA 134a in mild to moderate asthmatics. Eastern European study group.

The phasing out of chlorofluorocarbons (CFCs) requires the development of an alternative non-ozone depleting propellant for use in pressurized metered dose inhalers (pMDIs). The present study assessed the effects on tolerability and efficacy of a switch from the currently available formulation containing the CFC propellants 11 and 12 to an alternative non-CFC formulation using the propellant hydrofluoroalkane (HFA) 134a in patients with mild to moderate asthma. After a 4-week run-in period during which patients received salbutamol 200 microg four times daily from a CFC pMDI, 547 patients were randomized to 12 weeks of treatment with salbutamol 200 microg four times daily administered from either an HFA 134a pMDI (Ventolin CFC-free; 277 patients) or CFC pMDI (Ventolin, 270 patients). At the end of this period, all patients then received a further 4 weeks of treatment with the same dose of salbutamol via a CFC pMDI (run-out period). On the basis that high doses of beta2-agonists are known to increase heart rate, change in heart rate was selected as the primary outcome variable. Small increases in heart rate were observed during the treatment period and these changes were comparable in both groups; the 90% confidence interval for the treatment differences was within the predefined limits for clinical equivalence (+/- 10 beats min(-1)). The incidence of adverse events was similar in both groups and there were no reports of paradoxical bronchospasm. Furthermore, daily PEF measurements showed comparability in terms of lung function. Symptom scores and use of additional bronchodilator were also similar in both groups. These results demonstrate that salbutamol (800 microg day(-1)), formulated with HFA 134a is equivalent to the current CFC formulation in terms of tolerability and efficacy.

Clinical efficacy and safety of fluticasone propionate 1 mg per day administered via a HFA 134a pressurized metered dose inhaler to patients with moderate to severe asthma. International study group.

This multi-national, double-blind, randomized, parallel-group study compared the efficacy and tolerability of fluticasone propionate 500 microg twice daily propelled either by the non-chlorofluorocarbon (CFC) propellant, hydrofluoroalkane (HFA) 134a, or the CFC propellants 11 and 12 used in the established pressurized metered dose inhaler (pMDI). The study period was 12 months and involved 412 subjects with moderate to severe asthma (HFA 134a pMDI: n = 203; CFC pMDI: n = 209). For the first 3 months, subjects kept a daily record card and attended the clinic every 4 weeks. Thereafter, they kept daily diaries for 2 weeks before each clinic assessment, which were performed at the end of 6, 9 and 12 months. Mean morning peak expiratory flow (PEF) increased during the first week in both treatment groups. By the end of week 12 the adjusted mean increase from baseline in morning PEF was 21 and 23 l min(-1) in the HFA 134a and CFC pMDI groups, respectively, and this increase was maintained throughout the 12-month study period. Similar improvements were detected in other diary card parameters and in clinic lung function measurements. The two groups were shown to be clinically equivalent in terms of all efficacy variables and there were no differences in tolerability. There were few reports of low serum cortisol levels during the 12-month study period, and serum cortisol levels were similar at baseline and after 12 weeks and 12 months of treatment in the two groups. In conclusion, the new HFA 134a fluticasone propionate pMDI is as effective and safe as the established CFC fluticasone propionate pMDI when used at a dosage of 1 mg day(-1).

Clinical efficacy and safety of fluticasone propionate 1 mg twice daily administered via a HFA 134a pressurized metered dose inhaler to patients with severe asthma. U.K. study group.

A randomized, double-blind, cross-over study was conducted to assess the efficacy and safety of fluticasone propionate 1 mg twice daily administered via a pressurized metered dose inhaler (pMDI) containing the new non-chlorofluorocarbon (CFC) propellant (HFA 134a), or the established CFC propellants 11 and 12 in patients with severe asthma. The study comprised a 2-week run-in period followed by two 6-week treatment periods, with no washout period in between. One hundred and nineteen symptomatic adult patients with severe asthma, who were receiving inhaled beclomethasone 2-4 mg day(-1) or equivalent, were randomized to treatment. Patients were randomized to one of two sequence groups (sequence 1: HFA 134a pMDI then CFC pMDI or sequence 2: CFC pMDI then HFA 134a pMDI). The sequence groups differed with respect to mean peak expiratory flow (PEF) at baseline; however, the magnitude of the increase in PEF from baseline during treatment was similar in the two sequence groups. Mean PEF at baseline was 334 l min(-1) in sequence group 1 (HFA 134a-->CFC pMDI) and this increased to 357 l min(-1) and 366 l min(-1) during treatment with the HFA 134a and CFC pMDI, respectively. In sequence group 2 (CFC-->HFA 134a pMDI) mean PEF at baseline was 297 l min(-1) and this increased to 336 l min(-1) and 328 l min(-1) during treatment with the HFA 134a and CFC pMDI, respectively. Based on an overall analysis of the two treatment groups at week 6, equivalence was demonstrated; the mean treatment difference (HFA 134a-CFC pMDI) in morning PEF was 0 l min(-1) (90% confidence interval (CI), for difference between groups: -7, 6 l min(-1)). There was a comparable improvement in secondary efficacy variables, including clinic lung function measurements, in the two treatment groups. The incidence and type of most adverse events were similar in the two treatment groups. There was no difference in the adjusted geometric mean morning serum cortisol levels after treatment with the HFA 134a and CFC pMDI. Therefore, the fluticasone propionate HFA 134a pMDI constitutes a suitable replacement for the established CFC pMDI at a microgram equivalent dose.

The effect of an inhibitor of matrix metalloproteinases on colonic inflammation in a trinitrobenzenesulphonic acid rat model of inflammatory bowel disease.

BACKGROUND: Recent publications have reported that matrix metalloproteinases (MMPs) are expressed in colonic tissue taken from ulcerative colitis and Crohn's disease patients. AIM: To evaluate the effects of a matrix metalloproteinase inhibitor, marimastat, on colonic inflammation in experimental colitis induced by trinitrobenzenesulphonic acid (TNBS)-ethanol in the rat. METHODS: Rats were dosed (by mouth) for 7 days (b.d.) with either sulphasalazine (50 mg/kg), marimastat (40 mg/kg) or vehicle. TNBS-ethanol was administered rectally on the 4th day of dosing. On the last day of dosing, colons were removed and assessed for inflammation using myeloperoxidase activity, production of soluble TNFalpha (tumour necrosis factor alpha), clinical score and histological assessment. In addition, the bioavailability and effect of marimastat on a range of MMPs were assessed in-vitro. RESULTS: In this study we have confirmed that marimastat is a broad spectrum MMPI with a bioavailability of 5%. TNBS rats dosed with sulphasalazine had a significantly lower (P < 0.05) myeloperoxidase activity, TNFalpha production and a markedly lower clinical score. Similarly, rats dosed with marimastat had a significantly lower (P < 0.05) myeloperoxidase activity and clinical score, but the TNFalpha production was not significantly reduced. CONCLUSIONS: Dosing rats with TNBS-induced colitis using sulphasalazine or marimastat produced a significant reduction in tissue injury and inflammation.

Effect of fluticasone in severe polyposis.

OBJECTIVES: To investigate the effect of intranasal corticosteroids in the treatment of polyps in patients with severe polyposis listed for surgical treatment and to determine the treatment effect on the progression of the disease. DESIGN: A double-blind, randomized, parallel-group, placebo-controlled, 12-week study at a single center. SETTING: A tertiary referral center in London, England. PATIENTS: Thirty-four patients with severe polyposis listed for endoscopic surgical treatment. INTERVENTION: By random allocation, fluticasone propionate aqueous nasal spray (FPANS), 200 microg twice a day; beclomethasone dipropionate aqueous nasal spray, 200 microg twice a day; or placebo nasal spray twice a day was administered. Patients received 2 actuations to each nostril in the morning and in the evening. MAIN OUTCOME MEASURES: Efficacy end points were the need for polypectomy at the end of treatment, the results of acoustic rhinometry, the polyp score, the peak nasal inspiratory flow rate, and an assessment of symptoms. RESULTS: The polyp score was significantly decreased in the FPANS-treated group (P < or = .01). The nasal cavity volume was significantly increased in both the FPANS-treated group and the group receiving beclomethasone compared with placebo (P < or = .01) at the end of treatment. The percentage change in the mean morning peak nasal inspiratory flow rate was greater in the FPANS-treated group, with a significant effect observed at week 2 (P = .01). Nasal blockage was significantly decreased in both active groups compared with the group receiving placebo. No significant difference was observed between the treatment groups in the number of patients requiring polypectomy. CONCLUSIONS: Fluticasone and beclomethasone aqueous nasal sprays are effective in treating the symptoms of severe nasal polyps. There was some evidence that the group treated with FPANS responded more quickly to intervention and that the magnitude of the response was greater than in the group receiving beclomethasone.

Dipeptide transport and hydrolysis in rat small intestine, in vitro.

A range of natural and mixed D-/L-stereoisomer phenylalanine dipeptides was used to investigate peptide uptake and hydrolysis by isolated rings of rat jejunum. Characterisation of dipeptide hydrolysis by the brush border fraction revealed apparent Km values in the 0.1-1.0 mM range which, except for the charged dipeptides, were significantly higher than those for hydrolysis by the cytosolic fraction. Uptake of L-/L-dipeptides into jejunal rings, which was followed by HPLC, was unaffected by the presence of peptidase inhibitors in the incubation medium although the absorbed peptides were completely hydrolysed in the cytosol; comparison of the effects of excess leucine on dipeptide uptake and on the uptake of the two constituent amino acids were also consistent with absorption of intact dipeptide followed by cytosolic hydrolysis. The uptake of hydrolysis-resistant mixed D-/L-dipeptides was also studied and confirmed that peptide uptake preceded hydrolysis; D-alanyl-L-phenylalanine accumulated within the rings to twice the medium concentration.

Dipeptide transport and hydrolysis in isolated loops of rat small intestine: effects of stereospecificity.

1. Isolated jejunal loops of rat small intestine were perfused by a single pass of bicarbonate Krebs-Ringer solution containing either D- or L-phenylalanine or one of eight dipeptides formed from D- or L-alanine plus D- or L-phenylalanine. 2. At 0.5 mM L-phenylalanyl-L-alanine increased serosal phenylalanine appearance to forty times the control rate giving a value similar to that found with 0.5 mM free L-phenylalanine. No serosal dipeptide could be detected. 3. Perfusions with the two mixed dipeptides with N-terminal D-amino acids (D-alanyl-L-phenylalanine and D-phenylalanyl-L-alanine) gave rise to the appearance of intact dipeptides in the serosal secretions although there were substantial differences in their rates of absorption and subsequent hydrolysis. 4. L-Alanyl-D-phenylalanine was absorbed from the lumen three to five times as fast as L-phenylalanyl-D-alanine. At 1 mM L-alanyl-D-phenylalanine transferred D-phenylalanine across the epithelial layer at more than seven times the rate found with the same concentration of the free D-amino acid. 5. Perfusions with D-alanyl-D-phenylalanine or D-phenylalanyl-D-alanine showed that these two dipeptides are poor substrates for both transport and hydrolysis by the rat small intestine. 6. Analysis of mucosal tissue extracts after perfusion with the two mixed dipeptides with N-terminal D-amino acids revealed that both dipeptides were accumulated within the mucosa and suggested that exit across the basolateral membrane was rate limiting for transepithelial dipeptide transport.

Does aspiration of saliva trigger nocturnal asthma?

Five adult asthmatics with nocturnal symptoms (mean FEV1 2.31 1; 2 mean PD20 histamine 1.5 unmoles), 5 asthmatics with no nocturnal symptoms (mean FEV1 l 2.97 l; mean PD20 Histamine 3.7 unmoles) and 5 non-asthmatic control subjects (mean FEV1 3.63 l; mean PD20 histamine 78 unmoles) were challenged with nebulised solutions of their own saliva or isotonic saline in a double blind crossover study to investigate whether the inhalation of saliva during sleep could cause nocturnal asthma. The maximum % fall in FEV1 with saliva was -26.6, -6.5 and -4.1 for the nocturnal, non-nocturnal and control groups respectively. The corresponding values for the maximum % fall in FEV1 with saline was -12.4, -5.5 and -3.6. The difference in maximum % fall in FEV1 with both saliva and saline was significant (p < 0.01) for the nocturnal asthmatics when compared to the non-nocturnal asthmatics. These results lend support to the hypothesis that nocturnal symptoms in asthmatic patients may be triggered by inhalation of saliva during sleep.

Measurement of terbutaline and salbutamol in plasma by high performance liquid chromatography with fluorescence detection.

A method is described for the determination of terbutaline and salbutamol in plasma from patients given maximal therapy for brittle asthma. The analytes were isolated by solid phase extraction on alkali-treated Bond-Elut, unmodified, silica columns and measured by high performance liquid chromatography with fluorescence detection (excitation wavelength 200 nm). The limits of detection for a 1 mL sample containing salbutamol and terbutaline were 1 microgram/L and 2.5 micrograms/L, respectively. The intra-assay precision (CV) for samples containing 25 micrograms/L was 3.6 and 5.0% respectively. This method was applied to the measurement of terbutaline in samples from patients given continuous infusions of the drug to assess whether this treatment might result in toxicity.

Creatine kinase activity in patients with brittle asthma treated with long term subcutaneous terbutaline.

Infused beta 2 agonists have been shown to cause focal myocardial necrosis. Serum creatine kinase activity was compared in 13 patients with brittle asthma currently being treated with subcutaneous terbutaline and an age and sex matched control group of patients with moderate asthma having inhaled treatment only. The median serum total creatine kinase activity for patients receiving subcutaneous terbutaline (211 units/l) was greater than that for the control group (120 units/l). The cardiac specific isoenzyme component of creatine kinase was not raised in either group, and the electrocardiograms and serum aspartate aminotransferase activity were normal. Electromyograms in five patients receiving subcutaneous terbutaline with high creatine kinase activity showed changes consistent with myositis in two, one of whom was subsequently shown to have a metabolic myopathy, which is thought to be long standing. No pathological changes were seen in the myocardium at necropsy in a patient who died from an acute attack of asthma while taking subcutaneous terbutaline. These results suggest that the raised creatine kinase activity seen in patients receiving this treatment is unlikely to be myocardial in origin.

A study of the duration of the bronchodilator effect of 12 micrograms and 24 micrograms of inhaled formoterol and 200 micrograms inhaled salbutamol in asthma.

Formoterol is a new catecholamine analogue for which a longer duration of action is claimed. We studied the bronchodilator action of 12 micrograms and 24 micrograms of inhaled formoterol compared to 200 micrograms of inhaled salbutamol and placebo, in seven patients (mean age 59.3 yr) with moderate asthma. The adjusted mean peak rise in FEV1 was +0.331 each for salbutamol, 12 micrograms formoterol and 24 micrograms formoterol, all being significantly greater than that of placebo (+0.161; P less than 0.01). The duration of action was calculated in two ways. When calculating the time for the group mean FEV1 to return to baseline, the values were: for placebo, 3.1 h; salbutamol, 4.2 h; 12 micrograms formoterol, 6.8 h; and 24 micrograms formoterol, 11.2 h. When taking the times for each treatment at which individual FEV1 values returned to baseline and then calculating the adjusted mean time for each treatment group, the durations of action were: placebo, 3.5 h; salbutamol, 3.9 h; 12 micrograms formoterol, 5.9 h; and 24 micrograms formoterol, 8.1 h (24 micrograms formoterol compared to placebo, P = 0.02 and to 200 micrograms salbutamol, P = 0.03). The second method of calculation is nearer to a patient's approach in treating their asthma (i.e. taking an extra dose when needed), and may be a more realistic method of assessing duration of action. Formoterol is an effective bronchodilator, and the 24 micrograms dose should be assessed in the treatment of nocturnal asthma. In this group of older asthmatics with a degree of fixed airflow obstruction, we suggest that doses should be taken 8 hourly.