Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: a 16-week, randomized, double-blind, active control trial(*).

AIM: To assess and compare the efficacy and safety of liraglutide with those of glimepiride, both in combination with metformin for the treatment of type 2 diabetes in Asian population from China, South Korea and India. METHODS: A 16-week, randomized, double-blind, double-dummy, four-arm, active control trial was carried out. In total, 929 subjects with type 2 diabetes with a mean (±s.d.) age of 53.3 ± 9.5 years, HbA1(c) of 8.6 ± 1.0% and body weight of 68.1 ± 11.7 kg were randomized (liraglutide 0.6, 1.2 or 1.8 mg once daily or glimepiride 4 mg once daily all in combination with metformin: 1 : 1 : 1 : 1). One subject withdrew immediately after randomization and before exposure. RESULTS: HbA1(c) was significantly reduced in all groups compared with baseline. Treatment with liraglutide 1.2 and 1.8 mg was non-inferior to glimepiride (mean HbA1(c) reduction: 1.36% points, 1.45% points and 1.39% points, respectively). No significant difference was shown in the percentage of subjects reaching American Diabetes Association HbA1(c) target <7% or American Association of Clinical Endocrinologists target ≤6.5% between liraglutide 1.2 and 1.8 mg and glimepiride. Liraglutide was associated with a 1.8-2.4 kg mean weight reduction, compared with a 0.1 kg mean weight gain with glimepiride. Liraglutide led to a significantly greater reduction in systolic blood pressure (SBP) compared with glimepiride. Two subjects in the glimepiride group reported major hypoglycaemia while none in the liraglutide groups. Liraglutide was associated with about 10-fold lower incidence of minor hypoglycaemia than glimepiride. Gastrointestinal disorders were the most common adverse events (AEs) for liraglutide, but were transient and resulted in few withdrawals. CONCLUSIONS: In Asian subjects with type 2 diabetes, once-daily liraglutide led to improvement in glycaemic control similar to that with glimepiride but with less frequent major and minor hypoglycaemia. Liraglutide also induced a significant weight loss and reduced SBP and was generally well tolerated. The most frequently reported AE was transient nausea. The effect of liraglutide in this Asian population is comparable to the effects seen in Caucasian, African American and Hispanic populations in global liraglutide phase 3 trials.

Biphasic insulin aspart 30 treatment improves glycaemic control in patients with type 2 diabetes in a clinical practice setting: experience from the PRESENT study.

AIM: The Physicians' Routine Evaluation of Safety and Efficacy of NovoMix 30 Therapy (PRESENT) study aims to assess the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) in patients with type 2 diabetes mellitus in routine clinical practice. METHODS: This was a 6-month, prospective, multinational, multiethnic observational study involving 21 977 patients from 13 countries (India, Iraq, Jordan, Kuwait, Lebanon, Qatar, Romania, Russia, Saudi Arabia, South Africa, South Korea, Turkey and the United Arab Emirates). The patients were transferred to BIAsp 30 with or without oral antidiabetic drugs (OADs) from prior treatment with OAD (n = 8583), insulin (n = 5942), OAD + insulin (n = 4673) or diet (i.e. treatment naive) (n = 1707). One thousand and seventy-two patients had incomplete or no information on previous treatment. RESULTS: At 3 and 6 months, significant reductions from baseline were observed in the mean haemoglobin A(1c) (HbA(1c)) (-1.33 and -1.81%), fasting plasma glucose (-3.02 and -3.74 mmol/l) and postprandial plasma glucose (-4.76 and -5.82 mmol/l) (p < 0.001). A significantly greater proportion of patients achieved target HbA(1c) of less than 7% at 3 months (15.3%) and 6 months (27.7%) compared with baseline (4.8%) (p < 0.001). Overall, the mean HbA(1c) at 6 months was lowered in patients regardless of prior treatment: -2.15% (OAD), -1.45% (insulin), -1.47% (OAD + insulin) and -2.35% (treatment naive). In the overall cohort, the rate of total hypoglycaemia was reduced from 5.4 events per patient-year at baseline to 2.2 events per patient-year at study end (p < 0.001). Among prior treatment subgroups, the rates of total hypoglycaemia were reduced from 2.5 to 2.1 events per patient-year in the OAD group, from 9.6 to 2.2 events per patient-year in the insulin group and from 7.6 to 2.5 events per patient-year in the OAD + insulin group but were increased from 1.0 to 1.8 events per patient-year in the treatment-naive group (p < 0.001). There were 444 adverse drug reactions (ADRs), including 13 serious ADRs: lipodystrophy (three events), symptoms of generalized hypersensitivity (two events), acute painful neuropathy (one event), worsening of diabetic retinopathy (one event), oedema (one event) and unspecified ADRs (five events). CONCLUSION: The use of BIAsp 30 monotherapy or in combination with OADs in clinical practice was effective and safe in patients with poorly controlled type 2 diabetes mellitus.

Adding biphasic insulin aspart 30 once or twice daily is more efficacious than optimizing oral antidiabetic treatment in patients with type 2 diabetes.

AIM: To evaluate the efficacy and safety of adding biphasic insulin aspart 30 (BIAsp30; NovoMix 30) to existing oral antidiabetic agents (OADs) vs. optimizing OADs in a subgroup of Western Pacific patients with type 2 diabetes inadequately controlled on oral monotherapy or oral combination therapy. METHODS: This 26-week, multi-centre, open-labelled, randomized, two-arm parallel trial consisted of a 2-week screening period, followed by 24 weeks of treatment. Subjects randomized to BIAsp30 treatment (n = 129) received BIAsp30 once daily (o.d.) at dinnertime between Week 2 and Week 14, and those not reaching treatment targets were switched to twice daily (b.i.d.) BIAsp30 at Week 14 (n = 50). Subjects randomized to the OAD-only arm (n = 63) continued with their previous OAD treatment and, in an attempt to reach treatment goals, the dose was optimized (but OAD unchanged) in accordance to local treatment practice and labelling. RESULTS: Significantly greater reductions in HbA(1c) over Weeks 0-13 with BIAsp30 (o.d.) vs. OAD-only treatment (1.16 vs. 0.58%; p < 0.001), and over Weeks 0-26, with BIAsp30 (o.d.) and BIAsp30 (b.i.d.) treatments vs. OAD-only treatment (1.24 vs. 1.34 vs. 0.67%; p < 0.01). Hypoglycaemic episodes were reported in 54% of the patients in BIAsp30 (o.d. and b.i.d. pooled) and 30% of the patients in OAD-only group. All episodes were minor or symptomatic, except for one in each treatment group, which was major. CONCLUSIONS: Initiating BIAsp30 treatment is a safe and more effective way to improve glycaemic control in Western Pacific patients with type 2 diabetes inadequately controlled with oral monotherapy or oral combination therapy compared with optimizing oral combination therapy alone. In patients not reaching treatment target on BIAsp30 (o.d.), treatment with BIAsp30 (b.i.d.) should be considered.

Prevalence of clinical (major) depression in general practice using the DSM-IV version of PRIME-MD.

INTRODUCTION: PRIME-MD (Primary Care Evaluation of Mental Disorder) has been developed to detect the most frequent mental disorders in general practice. METHOD: A prevalence study with the Danish PRIME-MD's module for major depression was carried out by general practitioners. In total, 16 practices and 2501 patients were involved in the study. RESULTS: The patient questionnaire part of the PRIME-MD was completed by more than 95% of the patients, indicating a high applicability. Around 8% of all patients included suffered from major depression. Of these, the ratio of females to males was 2:1. Three factors were identified in the questionnaire: depression, psychosomatic distress, and alcohol use. Compared to the non-depressed patients, the patients with major depression evaluated their health condition as being considerably impaired. CONCLUSION: PRIME-MD is highly applicable in general practice. ( Int J Psych Clin Pract 2001; 5:49-54).

[Use of 5-aminolevulinic acid in photochemotherapy and fluorescence diagnostics]. / Bruk av 5-aminolevulinsyre i fotokjemoterapi og fluorescensdiagnostikk.

5-aminolevulinic acid is an early intermediate product in the synthesis of heme. Some of the enzymes in the heme synthesis chain have altered activities in tumor tissue, so that application of 5-aminolevulinic acid leads to an accumulation of protoporphyrin IX in tumors. This molecule absorbs light and acts as a potent photosensitizer; tumors containing the compound can therefore be destroyed by light. 5-aminolevulinic acid based photochemotherapy is presently being employed in the treatment of thin basal cell carcinomas in many countries. The cosmetic result of this treatment is excellent. Furthermore, it is a simple and inexpensive form of treatment with curative rates comparable to those of established therapy modalities. Experimentally, a number of other malignant lesions reachable by light via optical fibers are being treated. Since protoporphyrin IX has a characteristic red fluorescence, 5-aminolevulinic acid can also be applied for diagnostic purposes.

Protoporphyrin IX accumulation in cells treated with 5-aminolevulinic acid: dependence on cell density, cell size and cell cycle.

Human colon adenocarcinoma cells (WiDr) and Chinese hamster lung fibroblasts cells (V79) were incubated with different concentrations of 5-aminolevulinic acid (ALA), and the production of protoporphyrin IX (PpIX) was studied using several techniques. The amount of PpIX produced per cell increased with increasing ALA concentration according to different kinetics for the 2 cell lines. For both cell lines a cell density dependency of the PpIX synthesis was observed. For saturating ALA concentrations, 2-3 times more PpIX was produced per cell at a density of 5 x 10(4) than at a density of 5 x 10(3) cells/cm2. The photosensitivity of cells appeared to increase even more than the PpIX content, indicating a cooperative effect in inactivation. The PpIX production rate increased with cell size and was about 1.9 times higher for cells in the G2 + M phase than for cells in the G1 phase of the cell cycle. Neither cell size nor cell cycle distribution were significantly dependent on cell density.

The pH dependency of protoporphyrin IX formation in cells incubated with 5-aminolevulinic acid.

Chinese hamster cells (V79) and human adenocarcinoma cells (WiDr) were incubated with 5-aminolevulinic acid (ALA) at different pH values and the rate of production of protoporphyrin IX (PpIX) was measured. The rate of production increased with pH in the range 6.0-7.5. Above pH 7.5 the rate decreased, possibly due to a reduced metabolic activity of the cells. The observations may be explained by the known pH-dependency of the activity of porphobilinogen deaminase (PBGD) and are in agreement with the assumption that PBGD constitutes a rate-limiting step in the synthesis of PpIX from ALA.

Photobleaching of protoporphyrin IX in cells incubated with 5-aminolevulinic acid.

Protoporphyrin IX (Pp IX) is the main photosensitizer in photochemotherapy with 5-aminolevulinic acid (ALA). Pp IX is photolabile and the present work shows that 70-95% of Pp IX in cells is degraded by clinically relevant light exposures (40-200 J cm(-2) at 630 nm). During light exposure a small yield of photoprotoporphyrin, which is also photolabile, is formed. A substantial fraction of Pp IX in cells incubated with ALA is bound to proteins. During light exposure these binding sites are destroyed, those close to tryptophan residues being the most sensitive. The rate of photodegradation of Pp IX in the cells is dependent on the initial concentration of Pp IX. The degradation mechanisms are therefore not only first order processes. Different degradation rates appear to be related to different types of binding sites. During light exposure, Pp IX molecules appear to move to different binding sites, evidently sites that are more vital for cell survival. Thus, the yield of photoinactivation of the cells, as measured per emitted photon of Pp IX fluorescence, increased during light exposure.

A hydroxypyridinone (CP94) enhances protoporphyrin IX formation in 5-aminolaevulinic acid treated cells.

Different cell lines were given photodynamic treatment with 5-aminolaevulinic acid (ALA) and light. In addition, the iron chelator 1,2-diethyl-3-hydroxypyridin-4-one (CP94) was used. The porphyrin species produced was spectrofluorimetrically identified as protoporphyrin IX. All the cell lines responded to treatment, including a multidrug resistance gene expressing bladder cancer line and, to a lesser degree, cells derived from untransformed human skin fibroblasts. CP94 enhanced both porphyrin fluorescence, total porphyrin content and photosensitivity of the cells. CCD fluorescence microscopy showed a granular extranuclear porphyrin fluorescence distribution for all the cell lines involved, but the untransformed cells showed a distribution pattern different from the ones seen in the other cells.

The influence of iron chelators on the accumulation of protoporphyrin IX in 5-aminolaevulinic acid-treated cells.

Human adenocarcinoma cells of the line WiDr and Chinese hamster lung fibroblasts of the line V79 were treated with 5-aminolaevulinic acid (5-ALA) and exposed to light. The effects of the iron chelators ethylenediaminetetraacetic acid (EDTA) and desferrioxamine (DEF) were assessed. Both cell lines were treated with various concentrations of 5-ALA in the presence or absence of the iron chelators for 4 h in serum-free medium. The accumulation of protoporphyrin IX (PpIX) reached a maximum level at 1 mM 5-ALA in WiDr cells [280 ng PpIX (mg protein x 4 h-1] and at 0.1 mM 5-ALA in V79 cells [55 ng PpIX (mg protein x 4 h)-1]. PpIX was the only fluorescing porphyrin in these cells after 5-ALA treatment alone or in combination with the chelators. The iron chelators did not influence the intracellular localisation pattern of PpIX in 5-ALA-treated cells. While both chelators enhanced the accumulation of PpIX in 5-ALA-treated cells, DEF was found to be superior at equal concentrations. A linear relationship between the applied concentration of DEF and the DEF-induced increase in PpIX accumulation was observed in double-reciprocal plots. The intercepts of the regression lines with the ordinate indicate that the ferrochelatase is saturated with PpIX when the 5-ALA concentration exceeds 0.3 mM and 0.05 mM in WiDr and V79 cells respectively. The DEF-induced enhancement of PpIX accumulation in 5-ALA-treated cells was cell line and 5-ALA concentration dependent. At a 5-ALA concentration inducing a maximum level of PpIX accumulation, inhibition of ferrochelatase activity enhanced the PpIX accumulation 3- and 1.4-fold in V79 and WiDr cells respectively. The relative gain in PpIX accumulation increased with decreasing concentration of 5-ALA. In cells treated with the lowest concentrations of 5-ALA used in this study, DEF enhanced PpIX accumulation 44- and 3.5-fold in V79 and WiDr cells respectively. The iron chelator-induced increase in cellular PpIX accumulation was followed by a similar increase in sensitivity to photoinactivation. The ferrochelatase inhibitor dihydropyridine 3,5-diethoxycarbonyl-1,4-dihydrocollidine reduced the accumulation of PpIX in both cell lines.

A comparison of three diuretic regimens in heart failure.

Eight patients with mild heart failure were treated in random order for 1 week with 2 mg bumethanide at 0800 and 1200 (treatment 1) h, 1 mg bumethanide at 0800, 1200, 1800, 2200 (treatment 2) and 5 mg bendroflumethiazide at 0800 and 1800 (treatment 3) h. The 'quality of life' did not differ significantly between the three treatment periods. At the presumed trough of the diuretic effect the circulating blood volume was largest during treatment 1; it was 6.3% smaller during treatment 2 (P < 0.02) and 6.7% lower during treatment 3 (P < 0.05). In comparison with treatment 1, the maximal increase in rate-pressure product during physical exercise was 24.6% higher in treatment 3. Compared with treatment 1 the area under the curve (AUC) for plasma lactate during physical exercise was 14% lower during treatment 2 (P < 0.05) and 18% lower during treatment 3 (P < 0.01). These findings suggest that the type of program for diuretic therapy influences the magnitude of inevitable diurnal fluctuations in body fluids, the ability of the heart to work and the ability of the body to adjust to the oxygen demand.

Effects of long-term coenzyme Q10 and captopril treatment on survival and functional capacity in rats with experimentally induced heart infarction.

The effects of coenzyme Q10 (CoQ) and captopril on functional capacity, hemodynamics and survival were studied in 154 rats that recovered after experimental myocardial infarction. Rats were randomized into four groups receiving either CoQ, captopril, a combination of the two drugs or 1 ml of tap water once daily for 12 weeks from the day of coronary artery ligation. CoQ as well as captopril and the combined treatment significantly improved exercise capacity as evaluated by lactate production during a standardized treadmill exercise test. No significant changes in heart rate or mean blood pressure were observed during the study in the captopril-treated group. CoQ treatment increased the maximum heart rate significantly, whereas no effect on mean blood pressure was observed. Both captopril and CoQ decreased pulmonary congestion. Furthermore, the data may suggest that captopril prevents right ventricular hypertrophy seen in placebo-treated rats with large infarcts. This was not observed after CoQ treatment. Captopril treatment improved 3-month probability of survival (93%) as compared with placebo (74%) (P less than .05). CoQ and the combined treatment tended to improve survival, but this was, however, not statistically significant.

Time course of functional deterioration after coronary artery ligation in rats.

The aim of this study was to investigate the time course of deterioration of functional capacity in the rat after ligation of the left coronary artery. Functional capacity was evaluated from the increase in blood lactate concentrations in 109 rats during a standardised treadmill test. Animals with myocardial infarction were compared with sham operated and normal controls. Functional capacity was followed during a 13 week period and estimations of the functional capacity were performed 1, 3, 7, 9 and 13 weeks after infarction. Coronary artery ligation produced a significant reduction in functional capacity, averaging 47% (p less than 0.01) over the first 3 weeks after myocardial infarction, irrespective of infarct size. In rats with large infarcts, functional capacity remained essentially unchanged throughout the observation period, but rats with small infarcts improved gradually until their measured exercise response was completely normal at the end of the 13 week period.

Atrial content and plasma levels of atrial natriuretic peptides in rats with chronic renal failure.

The possible role of atrial natriuretic peptides (ANP) for the adaptive changes in renal Na excretion during chronic renal failure was studied in 5/6 nephrectomized (NX) rats maintained on a normal (100 mmol/kg) and a high (800 mmol/kg) Na diet. Atrial content of natriuretic substances was determined by bioassay and plasma ANP by radioimmunoassay. Nephrectomized rats showed a twofold increase in plasma ANP irrespective of their Na intake. Atrial ANP content was increased by high Na diet but unchanged by NX. Nephrectomized rats maintained on high Na diet showed partial depletion of atrial ANP stores. There were no significant changes in the volume fraction of atrial granules determined. The results suggest that ANP is involved in the regulation of renal Na excretion during chronic renal failure and acute Na loading; other mechanisms are probably involved in the adaption to chronic Na loading.