Associations of dietary macronutrient and fibre intake with glycaemia in individuals with Type 1 diabetes.

AIMS: To study the association between dietary intake and glycaemia in Type 1 diabetes. METHODS: Data on energy and nutrient intakes, and the mean and coefficient of variation of self-monitored blood glucose measurements were obtained from records completed by 1000 adults with Type 1 diabetes. Associations between these measures of glycaemia and dietary intake were investigated using generalized linear regression, with and without macronutrient substitution. RESULTS: In the first set of analyses, fibre intake was associated with lower mean self-monitored blood glucose values (ß = -0.428, 95% CI -0.624 to -0.231; P<0.001). In these same analyses, carbohydrate (ß = 0.011, 95% CI 0.002 to 0.020; P=0.014), alcohol (ß = 0.013, 95% CI 0.003 to 0.023; P=0.009) and monounsaturated fatty acid intakes (ß=0.012, 95% CI 0.001 to 0.023; P=0.029) were associated with higher variability in blood glucose measurements. In the macronutrient substitution analyses, substituting proteins for either carbohydrates (ß = -0.026, 95% CI -0.040 to -0.013; P<0.001), fats (ß = -0.018, 95% CI -0.033 to -0.004; P=0.014), or alcohol (ß = -0.026, 95% CI -0.045 to -0.006; P=0.010), or fats for carbohydrates (ß=-0.009, 95% CI -0.017 to -0.001; P=0.030), were all associated with lower variability in the measured blood glucose values. After adjusting for fibre intake, no significant results were observed in analyses of mean self-monitored blood glucose. CONCLUSIONS: This observational, cross-sectional study indicates that dietary fibre is associated with lower mean blood glucose concentrations in people with Type 1 diabetes. Glycaemic excursions were reduced when protein was substituted for other macronutrients and when fat replaced carbohydrate, after adjusting for fibre intake.

Hyperfiltration in type 1 diabetes: does it exist and does it matter for nephropathy?

AIMS/HYPOTHESIS: Hyperfiltration is widely regarded as a contributing factor to the development of microalbuminuria and progressive nephropathy in type 1 diabetes. However, recent studies have questioned this conclusion. METHODS: To address this conflicting evidence, we examined the association between hyperfiltration and progression to microalbuminuria in 2,318 adults with type 1 diabetes. We also compared the estimated GFR in our diabetic patients with rates observed in 6,247 adults from the Finnish general population, using age- and sex-specific z scores. RESULTS: The distribution of estimated GFR in adults with type 1 diabetes and normoalbuminuria was not significantly different from that expected in the general population (p = 0.51, Mann-Whitney test). Type 1 diabetic patients with a higher estimated GFR were also no more likely to develop microalbuminuria over a median of 5.2 years of follow-up than those with normal estimated GFR. This was the case regardless of whether hyperfiltration was defined by an absolute threshold, deciles of estimated GFR or a z score, using creatinine- or cystatin-based clearance formulas in men or in women. CONCLUSIONS/INTERPRETATION: Together with other studies, these data suggest that creatinine- or cystatin-based estimates of GFR do not predict the development of microalbuminuria in patients with type 1 diabetes. Moreover, in the absence of incipient or overt nephropathy, conventionally determined renal function in patients with type 1 diabetes appears no different from that in the general population. This is hardly surprising, given that these individuals, by all definitions, do not have kidney disease.

Purchase of antidepressant agents by patients with type 1 diabetes is associated with increased mortality rates in women but not in men.

AIMS/HYPOTHESIS: Individuals with diabetes have increased mortality rates compared with the general population. In patients with type 2 diabetes depression further contributes to the increased mortality. Depression and mortality rates in patients with type 1 diabetes are an understudied phenomenon. We therefore studied their association in a prospective setting. METHODS: We followed 4,174 participants (51% men, age 39 ± 12 years, diabetes duration 22 ± 12 years [mean ± SD]) in the Finnish Diabetic Nephropathy Study (FinnDiane) for an average of 9 years. Depression was defined as purchase of antidepressant agents at baseline and during follow-up. These data were obtained from the Finnish Drug Prescription Register. Data on all-cause mortality and cause of death were obtained from the Finnish Cause of Death Register. RESULTS: At baseline, 313 (7.5%) patients had purchased antidepressant agents. During follow-up 758 (18.2%) additional cases were observed. Purchasers of antidepressant agents at baseline had the highest 10-year cumulative mortality rate (22.5% [95% CI 18.1, 26.6]), followed by those with such purchases during follow-up (18.0% [15.4, 20.5]) and those with no purchases (10.1% [9.0, 11.2], p < 0.001). In the adjusted Cox regression models (age, diabetes duration, diastolic blood pressure, smoking, HbA(1c) and nephropathy), the purchase of antidepressant agents at baseline was associated with mortality in women, but not in men. Cardiovascular diseases were the major cause of death in non-purchasers of antidepressant agents. In antidepressant purchasers, chronic diabetic complications were the most frequent underlying cause of death. CONCLUSIONS/INTERPRETATION: In a population of patients with type 1 diabetes, purchase of antidepressant agents was associated with increased mortality rates in women, but not in men.

Evaluating the cost-effectiveness of reduced mild hypoglycaemia in subjects with Type 1 diabetes treated with insulin detemir or NPH insulin in Denmark, Sweden, Finland and the Netherlands.

AIMS: To estimate short-term cost-effectiveness of insulin detemir vs. NPH insulin based on the incidence of mild hypoglycaemia in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. METHODS: A model was developed to evaluate cost-effectiveness based on mild (self-treated) hypoglycaemia and pharmacy costs over 1 year. Published rates of mild hypoglycaemia were used for NPH insulin and insulin detemir. Effectiveness was calculated in terms of quality-adjusted life expectancy. Pharmacy costs were accounted using published prices and defined daily doses for both insulins. Costs were expressed in 2010 euros (€). RESULTS: Treatment with insulin detemir was associated with fewer mild hypoglycaemic events than NPH insulin (mean rates of 26.3 vs. 35.5 events per person-year), leading to an improvement in mean quality-adjusted life expectancy of approximately 0.019 (0.030) quality-adjusted life years (standard deviation). Annual costs were € 573.55 (110.42) vs. € 332.76 (62.18) in Denmark for insulin detemir and NPH insulin, respectively. These values were € 545.79 (106.54) vs. € 306.12 (57.78) in Sweden, € 720.10 (140.74) vs. € 408.73 (78.61) in Finland and € 584.01 (109.47) vs. € 359.60 (64.84) in the Netherlands. Incremental cost-effectiveness ratios were approximately € 12,644 (Denmark), € 12,612 (Sweden), € 16,568 (Finland) and € 12,216 (the Netherlands) per quality-adjusted life year gained for insulin detemir vs. NPH insulin. CONCLUSIONS: Insulin detemir is likely to be cost-effective vs. NPH insulin in subjects with Type 1 diabetes in Denmark, Sweden, Finland and the Netherlands. Increased pharmacy costs with insulin detemir should not be a barrier to therapy based on these findings.

Serum adiponectin concentration is a positive predictor of all-cause and cardiovascular mortality in type 1 diabetes.

BACKGROUND: Adiponectin is widely regarded as an anti-atherogenic, antioxidant and anti-inflammatory molecule. However, adiponectin concentration is paradoxically increased in individuals with type 1 diabetes, in whom it is positively associated with adverse clinical outcomes. OBJECTIVE: To explore the association between serum adiponectin concentration and mortality outcomes in adults with type 1 diabetes. DESIGN: Multicentre prospective cohort study. SETTING: Primary and tertiary care. SUBJECTS: Finnish adults with type 1 diabetes (n= 2034). Main outcome measures. All-cause and cardiovascular mortality. Independent predictors of mortality were determined using the Cox and the Fine and Gray competing risks proportional hazards models. RESULTS: During a median of 11 years of follow-up, there were 173 deaths (8.5%, 1.0 per hundred person-years). Adiponectin was linearly associated with all-cause mortality [Cox model: hazard ratio (HR) 1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and cardiovascular mortality (Fine and Gray model: HR 1.02, 95% CI 1.00-1.04, P=0.035); patients with the highest adiponectin concentrations had the shortest survival. The mortality risk associated with adiponectin was independent of glycaemic and lipid control, pre-existing cardiovascular disease, markers of inflammation and the presence and severity of kidney disease. CONCLUSIONS: Although adiponectin is generally considered to be a protective molecule, increased concentrations of adiponectin in type 1 diabetes are independently associated with all-cause and cardiovascular mortality. Moreover, the fact that this association was observed for the first time in patients with normal urinary albumin levels, who have few comorbidities, suggests that adiponectin is specifically linked with vascular damage in type 1 diabetes.

Association between mannose-binding lectin, high-sensitivity C-reactive protein and the progression of diabetic nephropathy in type 1 diabetes.

AIMS/HYPOTHESIS: Diabetic nephropathy has been associated with low-grade inflammation and activation of the complement system in cross-sectional studies. Data from prospective studies are sparse. We investigated the associations of the complement activator mannose-binding lectin (MBL) and the inflammatory marker high-sensitivity C-reactive protein (hsCRP) with the development of nephropathy in a large prospective study of patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study. METHODS: Baseline MBL and hsCRP were measured in 1,564 type 1 diabetes patients from the FinnDiane study, of whom 1,010 had a normal albumin excretion rate, 236 had microalbuminuria and 318 had macroalbuminuria. The main outcome was progression in renal disease during follow-up. RESULTS: Both baseline MBL (p = 0.038) and hsCRP (p < 0.001) increased with increasing level of albuminuria. During 5.8 +/- 2.2 years of follow-up, progression to a higher albuminuria level or end-stage renal disease (ESRD) occurred in 201 patients. MBL levels were higher in progressors compared with non-progressors at all steps of progression, and in a covariate adjusted multivariate Cox-regression analysis MBL levels above the median were significantly associated with progression from macroalbuminuria to ESRD (hazard ratio 1.88, 95% CI 1.06-3.32, p = 0.030). In a univariate analysis, hsCRP levels above the median were significantly associated with progression from normal albumin excretion rate to microalbuminuria, but the association was only borderline significant after adjustment for covariates (hazard ratio 1.56, 95% CI 0.97-2.51, p = 0.068). CONCLUSIONS/INTERPRETATION: This study demonstrates that concentrations of both MBL and hsCRP are associated with the progression of renal disease in type 1 diabetes.

Lipid abnormalities predict progression of renal disease in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We studied the impact of baseline lipid variables on the progression of renal disease in a large nationwide prospective cohort of patients with type 1 diabetes. METHODS: A total of 2,304 adult patients with type 1 diabetes and available lipid profiles participating in the Finnish Diabetic Nephropathy Study (FinnDiane) were evaluated. Data on progression of renal disease were verified from medical files and patients were followed for 5.4 +/- 2.0 (mean +/- SD) years. RESULTS: High triacylglycerol, apolipoprotein (Apo) B, ApoA-II and HDL(3)-cholesterol concentrations predicted incident microalbuminuria. Progression to macroalbuminuria was predicted by high triacylglycerol and ApoB. When AER was entered into the model, triacylglycerol was no longer an independent predictor, but when patients with normal AER and microalbuminuria at baseline were pooled, triacylglycerol, HbA(1c), male sex and AER were all independent predictors of renal disease. High total cholesterol, LDL-cholesterol, non-HDL-cholesterol and triacylglycerol as well as low HDL-cholesterol, HDL(2)-cholesterol, ApoA-I and ApoA-II concentrations were predictive of progression to end-stage renal disease. However, when estimated GFR was entered into the model, only total cholesterol remained an independent predictor of progression. CONCLUSIONS/INTERPRETATION: Lipid abnormalities, particularly high triacylglycerol concentrations, increase the risk of progression of renal disease.

Glucose variability, blood pressure and arterial stiffness in type 1 diabetes.

AIMS: Evidence suggests that chronic hyperglycaemia predicts not only microvascular disease but also macrovascular disease, however it is not known whether it is the glucose variability per se or the total glucose exposure that confers risk. The objective of this study was to investigate whether daily glucose variability influence blood pressure and arterial stiffness, an early sign of macrovascular disease, at baseline and during a hyperglycaemic clamp in patients with type 1 diabetes. METHODS: Twenty-two non-smoking male patients with type 1 diabetes without any diabetic complications, participated in the study. The patients were monitored for 72-h using a continuous glucose monitoring system. Before and during a 2-h hyperglycaemic clamp, blood pressure as well as pulse wave analysis and pulse wave velocity (PWV) were performed to assess arterial stiffness. RESULTS: No correlation was observed between mean amplitude of glycaemic excursions (MAGE) and arterial stiffness at baseline. There was a correlation between mean daily glucose and aortic PWV even after adjusting for BMI, HbA(1c), and duration of diabetes in a multiple regression analysis (r=0.48; P<0.01). MAGE (r=0.52; P<0.01) correlated independently with the change in aortic DBP during the clamp. CONCLUSIONS: This study suggests that high mean daily blood glucose but not glucose variability per se is associated with arterial stiffness in patients with T1D. Daily glucose variability is positively associated with the change in central blood pressure during a hyperglycaemic clamp.

Relationship between lipid profiles and kidney function in patients with type 1 diabetes.

AIMS/HYPOTHESIS: We studied the relationship between the lipid profile, estimated GFR (eGFR) and AER in patients with type 1 diabetes. We also assessed the association between the lipid profile and glycaemic control, obesity and hypertension in an environment free of manifest renal disease, as well as exploring how well the patients would have achieved the targets set in international guidelines. METHODS: A total of 2,927 adult patients who had type 1 diabetes and for whom lipid profiles were available were included from people participating in the nationwide, multicentre Finnish Diabetic Nephropathy Study (FinnDiane). eGFR was determined using the Cockcroft-Gault formula adjusted for body surface area. RESULTS: Patients with impaired renal function (eGFR <60 ml min(-1) 1.73 m(-2)) had higher total cholesterol, triacylglycerol and apolipoprotein B, and lower HDL-cholesterol concentrations than patients with normal renal function (eGFR >90 ml min(-1) 1.73 m(-2)) or mildly impaired renal function (eGFR 60-90 ml min(-1) 1.73 m(-2)) (p < 0.001 for all associations). In type 1 diabetic patients without manifest renal disease, similar adverse lipid profiles could be observed in those who were overweight or obese and in those who had intermediate or poor glycaemic control or hypertension. In all the different patient groups 14 to 43% would have achieved the recommended target of <2.6 mmol/l for LDL-cholesterol. CONCLUSIONS/INTERPRETATION: Multiple lipid abnormalities are not only present in type 1 diabetic patients with an abnormal AER, but also in those with impaired renal function. In patients without manifest renal disease, obesity, glycaemic control or hypertension were associated with an adverse lipid profile. A substantial number of patients studied would have exceeded the targets set by international guidelines, particularly the targets for LDL-cholesterol.

Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy.

OBJECTIVE: Diabetic nephropathy is associated with low-grade inflammation and activation of the complement system. Defensins, as part of the innate immune system, may play a regulatory role in the complement cascade and may also augment the production of proinflammatory cytokines. The aim of this study was therefore to elucidate whether alpha-defensin is associated with diabetic nephropathy, low-grade inflammation and lipid profiles. RESEARCH DESIGN AND METHODS: Data were obtained from 189 patients with type 1 diabetes selected from the FinnDiane Study. Patients were divided into three groups according to their albumin excretion rate (AER) in three consecutive overnight or 24-h urine collections: normoalbuminuria (AER <20 microg/min or <30 mg/24 h), microalbuminuria (20 200 microg/min or >300 mg/24 h). Alpha-defensin was determined by a novel, solid-phase radioimmunoassay (RIA) based on a monoclonal antibody, which recognizes alpha-defensin isoforms 1-3. RESULTS: Total serum alpha-defensin (-1, -2 and -3) concentrations were higher (P < 0.001) in patients with macroalbuminuria compared to micro- and normoalbuminuria, but no difference was observed between normoalbuminuria and microalbuminuria. In multiple linear regression analysis alpha-defensin was associated with systolic blood pressure (P = 0.032), HDL-cholesterol (P = 0.013), total cholesterol (P = 0.008), age (P = 0.001) and estimated glomerular filtration rate (P = 0.001), but not with low-grade inflammatory markers. CONCLUSIONS; Serum alpha-defensin (-1, -2 and -3) concentrations are increased in type 1 diabetic patients with diabetic nephropathy.

Acute hyperglycaemia rapidly increases arterial stiffness in young patients with type 1 diabetes.

AIMS/HYPOTHESIS: Augmentation index (AIx) and pulse wave velocity (PWV), both measures of arterial stiffness, constitute risk factors for cardiovascular disease. Notably, hyperglycaemia during an acute cardiovascular event is associated with poor prognosis. The objective of this study was to investigate whether acute hyperglycaemia increases arterial stiffness in patients with type 1 diabetes and in healthy subjects. METHODS: Twenty-two male patients with type 1 diabetes and thirteen healthy men, who were age-matched non-smokers and without any diabetic complications, underwent a 120 min hyperglycaemic clamp (15 mmol/l). AIx was calculated to assess arterial stiffness. Before and during the clamp, carotid-radial (brachial) and carotid-femoral (aortic) PWV was measured. RESULTS: At baseline there was a difference in the AIx between patients with type 1 diabetes and healthy volunteers (-5 +/- 2.7 vs -20 +/- 2.8%, p < 0.05). Acute hyperglycaemia rapidly increased AIx in patients with type 1 diabetes (-5 +/- 2.7 vs 8 +/- 2.5%, p < 0.001) and healthy volunteers (-20 +/- 2.8 vs 6 +/- 8.8%, p < 0.001). Brachial PWV increased during acute hyperglycaemia in patients with type 1 diabetes (7.1 +/- 1.2 vs 8.0 +/- 1.0 m/s, p < 0.001), but not in healthy men (7.4 +/- 1.7 vs 7.3 +/- 1.4 m/s, NS). CONCLUSIONS/INTERPRETATION: Acute hyperglycaemia increases the stiffness of intermediate-sized arteries and resistance arteries in young patients with type 1 diabetes and consequently emphasises the importance of strict daily glycaemic control. No change was observed in aortic PWV during the clamp, indicating that acute hyperglycaemia does not affect the large vessels.

Increased levels of mannan-binding lectin in type 1 diabetic patients with incipient and overt nephropathy.

AIMS/HYPOTHESIS: Diabetic nephropathy is associated with insulin resistance, and low-grade inflammation and activation of the complement system may contribute to this cascade. Mannan-binding lectin (MBL) activates the complement system, and elevated MBL concentrations have been observed in normoalbuminuric type 1 diabetic patients. The aim of this study was to assess whether MBL is associated with diabetic nephropathy in type 1 diabetes, and whether there is an association between MBL and low-grade inflammatory markers or insulin resistance. METHODS: A total of 191 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based upon their AER. Patients with normal AER (n=67) did not take antihypertensive medication, while patients with microalbuminuria (n=62) or macroalbuminuria (n=62) were all treated with an ACE inhibitor. As a measure of insulin sensitivity we used estimated glucose disposal rate. MBL was measured by an immunofluorometric assay, C-reactive protein by a radioimmunoassay and IL-6 by high-sensitivity enzyme immunoassay. RESULTS: Patients with normal AER (median [interquartile range]: 1,154 microg/l [180-2,202 microg/l]) had lower levels of MBL than patients with microalbuminuria (1,713 microg/l [724-2,760 microg/l]; p=0.029) or macroalbuminuria (1,648 microg/l [568-3,394 microg/l]; p=0.019). There was a significant correlation between MBL and estimated glucose disposal rate, but not between MBL and C-reactive protein or IL-6 levels in univariate analysis. However, in a multiple regression analysis, HbA1c was the single variable independently associated with MBL (beta+/-SEM: 0.26+/-0.08; p=0.003). CONCLUSIONS/INTERPRETATION: MBL concentrations are increased in type 1 diabetic patients with diabetic nephropathy. MBL was not associated with low-grade inflammatory markers.

Diabetic nephropathy is associated with low-grade inflammation in Type 1 diabetic patients.

AIMS/HYPOTHESIS: Increased concentrations of C-reactive protein and interleukin-6, a finding suggestive of the presence of inflammation, have been observed in Type 2 diabetes. In such patients, C-reactive protein was predictive of diabetic nephropathy. Studies on low-grade inflammatory markers and nephropathy in Type 1 diabetic patients have shown conflicting results. Therefore we studied whether low-grade inflammation is associated with diabetic nephropathy in Type 1 diabetic patients. METHODS: We divided 194 Type 1 diabetic patients into three groups from the Finnish Diabetic Nephropathy Study based upon their albumin excretion rate. Patients with normoalbuminuria (n=67) had no antihypertensive medication or signs of cardiovascular disease, while patients with microalbuminuria (n=64) or macroalbuminuria (n=63) were all treated with an angiotensin-converting enzyme inhibitor, a drug that could attenuate low-grade inflammation. As a measure of insulin sensitivity we used estimated glucose disposal rate. C-reactive protein was measured by radioimmunoassay and interleukin-6 by high sensitivity enzyme immunoassay. RESULTS: C-reactive protein was higher in micro- and macroalbuminuric patients compared to normoalbuminuric patients (normoalbuminuria 2.0+/-1.7, microalbuminuria 2.6+/-1.7, macroalbuminuria 2.9+/-2.5 mg/l; p=0.016), while interleukin-6 increased in parallel with the severity of the renal disease (1.9+/-1.5, 2.9+/-3.3, 3.6+/-3.1 ng/l; p<0.0001). In multiple regression analysis albumin excretion rate was the only variable independently associated with C-reactive protein (p=0.03), whereas albumin excretion rate (p=0.0003), HDL-cholesterol (p=0.0135) and duration of diabetes (p=0.0176) were independently associated with interleukin-6. CONCLUSIONS/INTERPRETATION: Low-grade inflammatory markers are associated with diabetic nephropathy in Type 1 diabetic patients. The predictive value needs to be assessed.

Pharmacokinetics of entacapone, a peripherally acting catechol-O-methyltransferase inhibitor, in man. A study using a stable isotope techique.

OBJECTIVE: This study investigated the pharmacokinetics of the catechol-O-methyltransferase (COMT) inhibitor entacapone by giving simultaneously stable non-radioactive isotope 13C-entacapone intravenously (i.v.) and unlabelled entacapone orally. In comparison with a crossover design, the simultaneous i.v. and oral administration made it possible to minimise intra-individual variation, sample size and the duration of the study and still obtain accurate pharmacokinetic data. METHODS: Eight healthy male volunteers were enrolled in this study. They were given a 20-mg i.v. dose of 13C-entacapone as a 1-mg/ml infusion at a constant rate of 5 mg/min over 4 min and a 100-mg dose of unlabelled entacapone orally immediately after the infusion. Blood samples were drawn at -5 (before onset of infusion), 0 (upon termination of infusion), 2, 5, 10, 20, 30 and 45 min and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10 and 12 h after the tablet ingestion. Urine during the 48 h after dosing was collected in fractions. Concentrations of 13C-entacapone and entacapone in plasma samples and urine fractions were determined using gas chromatography-mass spectrometry. RESULTS: The decay of i.v. 13C-entacapone in plasma was tri-exponential and its pharmacokinetics were described using an open three-compartment model. The volume of the central compartment (Vc) and the volume of distribution at steady state (Vss) were 0.08+/-0.03 l/kg and 0.27+/-0.10 l/kg, respectively. Total plasma clearance (Cltot) averaged 11.7+/-1.9 ml/min kg(-1). The half-lives for the distribution phase and for the rapid and terminal elimination phases (t1/2alpha, t1/2beta and t1/2gamma) were 0.05+/-0.01 h, 0.38+/-0.16 h and 2.40+/-1.70 h, respectively. The terminal elimination phase accounted for only 9% of the total area under the plasma concentration-time curve (AUC), which was 409 +/- 98 ng h/ml after the i.v. dose. Oral entacapone was absorbed rapidly with a time to reach the peak concentration (tmax) of 0.9+/-0.4 h, a maximum concentration (Cmax) of 457+/-334 ng/ml and an AUC of 497+/-118 ng h/ml. During the 48 h after dosing, the recovery of free and conjugated unchanged 13C-entacapone in urine was 38.1+/-7.2% of the i.v. dose and the recovery of free and conjugated unchanged entacapone 13.3+/-3.9% of the oral dose. The bioavailability of oral entacapone was 25% based on the AUC values and 35% based on urinary excretion. CONCLUSION: The results of the present study using stable isotope technique indicate that entacapone is rapidly absorbed, distributed to a small volume and rapidly eliminated by mainly non-renal routes. The pharmacokinetic profile of entacapone provides the rationale for a concomitant and frequently repeated simultaneous dosing of entacapone with levodopa and dopa decarboxylase inhibitors in the treatment of Parkinson's disease. This study confirmed the previously published data and fully support the validity of the technique used.

Comparative pharmacokinetics of lovastatin, simvastatin and pravastatin in humans.

Twelve healthy male volunteers received single market-image 40-mg oral doses of lovastatin and simvastatin (both lactone prodrugs), or pravastatin (a beta-hydroxyacid) at 1 week intervals in a three-way crossover study to quantify HMG-CoA reductase inhibitors in plasma. Multiple plasma samples were collected up to 24 hours after the dose and assayed for active and total HMG-CoA reductase inhibitors. After equal oral doses, higher plasma concentrations of HMG-CoA reductase inhibitory activity after pravastatin than after either lovastatin of simvastatin (2-3 fold greater area under the concentration-time curve) suggest a greater potential availability of pravastatin-related inhibitory activity to peripheral tissues.