Novel Microneedle Patches for Active Insulin Delivery are Efficient in Maintaining Glycaemic Control: An Initial Comparison with Subcutaneous Administration

Purpose Good glycaemic control is essential to minimize the risk for diabetes-induced complications. Also, compliance is likely to be higher if the procedure is simple and painless. This study was designed to validate painless intradermal delivery via a patch-like microneedle array. Materials and Methods Diabetes was induced by an intravenous injection of streptozotocin (50 mg/kg bw) in adult male Sprague Dawley rats. Plasma insulin and blood glucose were measured before, during and after subcutaneous or intradermal (microneedles) infusion of insulin (0.2 IU/h) under Inactin-anaesthesia. Results Before insulin administration, all animals displayed a pronounced hyperglycaemia (19 ± 1 mM; 359 mg/dl). Administration of insulin resulted in a reduced plasma glucose independently of administration route (subcutaneous 7.5 ± 4.2, n = 9, and intradermal 11 ± 1.8, n = 9 after 240 min), but with less errors of the mean in the intradermal group. In the intradermal group, plasma insulin was increased in all latter measurements (72 ± 22, 81 ± 34, and 87 ± 20 μIU/ml), as compared to the first measurement (26 ± 13). In the subcutaneous group, plasma insulin was elevated during the last measurement (to 154 ± 3.5 μIU/ml from 21 ± 18). Conclusion This study presents a novel possibility of insulin delivery that is controllable and requires minimal training. This treatment strategy could improve compliance, and thus be beneficial for patients’ glycaemic control.     

Pharmacokinetics and pharmacodynamics of a premixed formulation of soluble and protamine-retarded insulin aspart

Objective: With the aim to obtain a premixed rapid-acting insulin with a serum insulin profile more closely resembling the endogenous meal-stimulated serum insulin profiles, a 30/70 (rapid/intermediate-acting) premixed suspension of the rapid-acting insulin analogue insulin aspart (BIAsp30) was compared with a similar premixed suspension of biphasic human insulin 30/70 (BHI30) after a single subcutaneous injection. Methods: The study had a randomised, double-blind, two-period crossover design. Twenty-four healthy male subjects received a single subcutaneous dose of either 0.2 U · kg⁻¹ bodyweight of BIAsp30 or BHI30 on two study days. Results: BIAsp30 was absorbed faster than BHI30, as reflected in the area under the insulin concentration-time curve from 0 to 90 min after dosing [AUC_{(0–90 min)}]. This was significantly larger for BIAsp30 than for BHI30 (1403 ± 372 versus 752 ± 191 mU · l⁻¹ · min⁻¹ [mean ± SD]; P < 0.0001). Furthermore, the time to maximum serum insulin concentration (t_max) of BIAsp30 was approximately half the t_max of BHI30 (60 [45–70] versus 110 [90–180] min [median, interquartile range]; P=0.0001) and the maximum insulin concentration (C_max) was significantly higher for BIAsp30 than for BHI30 (23.4 ± 5.3 versus 15.5 ± 3.7 mU · l⁻¹ [mean ± SD]; P < 0.0001). The serum glucose profiles showed a significantly earlier onset of the glucose-lowering effect following BIAsp30 than following BHI30. Conclusions: The improved absorption properties of soluble insulin aspart in its premixed formulation provide a basis for a more efficient meal-related glucose control and immediate pre-meal delivery when compared with a similar human premixed insulin in the treatment of diabetes mellitus. Received: 22 November 1999 / Accepted in revised form: 7 April 2000     

Pharmacodynamics and pharmacokinetics of intravenous glibenclamide in Caucasian and Chinese patients with type-2 diabetes

Objective: We analysed the kinetics and effects of glibenclamide (Gb) on glucose, insulin and proinsulin secretion in two ethnic groups (10 in each) of type-2 diabetic patients, one of Caucasian, the other of Chinese origin. Background: Diabetes mellitus type 2 is a global disease affecting all ethnic groups. There are ethnic differences in both the prevalence and metabolic characteristics of the disease. Important interethnic pharmacodynamic and pharmacokinetic differences have been reported for several drugs. With few exceptions, detailed studies on sulphonylurea are lacking. Material and methods: The patients were studied on two occasions when either no Gb (control) or 1.25 mg Gb was administered i.v., immediately before the administration of a 75-g oral glucose tolerance test. Concentrations of insulin and proinsulin were determined by means of radioimmunoassay without cross-reactivities. Gb concentration was determined using high-performance liquid chromatography. Pharmacodynamic results were calculated using net areas under the curves, with basal values set as zero. A P value less than 0.05 was considered significant. Results: When glucose was administered orally without Gb, Chinese patients had higher plasma glucose increases at 10 min (7.6 mmol/l × min vs 2.6 mmol/l × min) and higher increases of plasma insulin levels than Caucasians at both 10 min (198 pmol/l × min vs 54 pmol/l × min) and 30 min (2286 pmol/l × min vs 1198 pmol/l × min). When Gb was administered, the plasma glucose increases were reduced, and the increases of serum insulin and proinsulin levels were greater in both ethnic groups. Compared with the basal values (−1 min), proinsulin/insulin ratios (RPI) were lowest at 10–30 min, followed by an increase. Chinese patients had higher increases of serum insulin levels at 10 min (1109 pmol/l × min vs 550 pmol/l × min) and a lower RPI at 30 min (6.0% vs 7.6%) and 240 min (15.0% vs 21.0%) relative to Caucasians. Serum Gb data were best fitted to a biexponential i.v. model. There were no interethnic differences in any of the pharmacokinetic parameters. Conclusion: In summary, following oral glucose administration without Gb, Chinese type-2 diabetic patients had higher plasma insulin levels but also higher plasma glucose levels during the first 10 min, which might reflect reduced insulin sensitivity or more rapid glucose absorption. Gb augmented glucose-induced release of both insulin and proinsulin in both ethnic groups; the effect on insulin secretion was more pronounced. In conclusion, minor pharmacodynamic but no pharmacokinetic differences were found between the two groups. It seems appropriate to employ the same dosage principles when using Gb in Caucasians and Chinese. Received: 15 June 1999 / Accepted in revised form: 9 August 1999     

Chronic colchicine treatment does not impair glucose tolerance in familial Mediterranean fever patients

Objective: To investigate a long-term colchicine treatment in inhibiting normal release of insulin, in response to a glucose load. Setting: The Heller Institute of Medical Research, Sheba Medical Center, Tel-Hashomer. Patients: Thirty-one familial Mediterranean fever (FMF) patients, treated continuously with colchicine (1.0–2.0 mg · day^–1) for 2–13 years. Methods: A standard oral glucose tolerance test (OGTT) was performed to study the effect of long-term colchicine treatment on glucose-induced insulin response. An intravenous glucose tolerance test (IVGTT) was then performed on randomly chosen FMF patients (n = 9) and age-matched controls (n = 5). Glucose was administered 30 min after intravenous colchicine (2 mg) infusion. The sum of 1st- and 3rd-min insulin levels served as an index of early-phase insulin release. Results: Based on the Office Guide to Diagnosis of Glucose Intolerance [13], one subject exhibited impaired glucose tolerance and two others had abnormal dynamics of glucose during the test but normal values at 120 min. Insulin values were normal in all participants. No significant differences were found in maximal glucose and insulin concentration, nor in the insulin release index between FMF colchicine-treated and healthy controls. Conclusions: Based on these findings, no impairment in glucose dynamics could be demonstrated in chronically colchicine treated patients, compared to untreated controls. Received: 28 August 1995 / Accepted in revised form: 24 October 1996     

Transdermal Delivery of Interferon Alpha-2B using Microporation and Iontophoresis in Hairless Rats

Purpose To demonstrate transdermal delivery of interferon alpha-2b (IFNα2b) in hairless rats through aqueous microchannels (micropores) created in the skin and enhanced by iontophoresis. Materials and Methods The Altea Therapeutics PassPort™ System was configured to form an array of micropores (2.0 cm²; 72 micropores/cm²) on the rat abdomen. The transdermal patch (Iomed TransQ1-GS-hydrogel) was saturated with an IFNα2b solution (600 μg/ml) and applied for 4 h. Delivery was evaluated with and without cathodic iontophoresis (0.1 mA/cm²). Intravenous delivery (0.4 μg/100 g body weight) was performed to support pharmacokinetic calculations. Results IFNα2b was not delivered through intact skin by itself (passive delivery) or during iontophoresis. However, passive delivery through micropores was achieved in vivo in rats. A dose of 397 ± 67 ng was delivered over 6 h, with steady state serum concentrations reaching a plateau at 1 h post-patch application. These levels dropped rapidly after patch removal, and returned to baseline within 2 h of patch removal. Iontophoresis-enhanced delivery through micropores resulted in a two-fold increase in the dose delivered (722 ± 169 ng) in the hairless rat. Conclusions In vivo delivery of IFNα2b was demonstrated through micropores created in the outer layer of the skin. Iontophoresis enhanced delivery through microporated skin in hairless rats.     

Transdermal Delivery of Cytochrome C—A 12.4 kDa Protein—Across Intact Skin by Constant–Current Iontophoresis

Purpose To demonstrate the transdermal iontophoretic delivery of a small (12.4 kDa) protein across intact skin. Materials and Methods The iontophoretic transport of Cytochrome c (Cyt c) across porcine ear skin in vitro was investigated and quantified by HPLC. The effect of protein concentration (0.35 and 0.7 mM), current density (0.15, 0.3 or 0.5 mA.cm⁻² applied for 8 h) and competing ions was evaluated. Co-iontophoresis of acetaminophen was employed to quantify the respective contributions of electromigration (EM) and electroosmosis (EO). Results The data confirmed the transdermal iontophoretic delivery of intact Cyt c. Electromigration was the principal transport mechanism, accounting for ∼90% of delivery; correlation between EM flux and electrophoretic mobility was consistent with earlier results using small molecules. Modest EO inhibition was observed at 0.5 mA.cm⁻². Cumulative permeation at 0.3 and 0.5 mA.cm⁻² was significantly greater than that at 0.15 mA.cm⁻²; fluxes using 0.35 and 0.7 mM Cyt c in the absence of competing ions (J _tot  = 182.8 ± 56.8 and 265.2 ± 149.1 μg.cm⁻².h⁻¹, respectively) were statistically equivalent. Formulation in PBS (pH 8.2) confirmed the impact of competing charge carriers; inclusion of ∼170 mM Na⁺ resulted in a 3.9-fold decrease in total flux. Conclusions Significant amounts (∼0.9 mg.cm⁻² over 8 h) of Cyt c were delivered non-invasively across intact skin by transdermal electrotransport.     

Comparative pharmacokinetics and pharmacodynamics of the novel rapid-acting insulin analogue, insulin aspart, in healthy volunteers

Objective: The pharmacokinetics of a new insulin analogue, insulin aspart, were compared with unmodified human insulin in a double-blind crossover study of 25 fasting healthy men following a single subcutaneous dose. Methods: Either insulin aspart or human insulin, 0.1 U · kg-body-weight⁻¹, was injected subcutaneously and followed by determination of 8-h profiles of serum insulin and plasma glucose concentrations. Results: The absorption of insulin aspart was, on average, more than twice as fast and reached levels more than twice as high compared with human insulin [t_max(ins) of 52 (23) vs 145 (93) min, P < 0.0001; and C_max(ins) of 41 (11) vs 18 (4) mU · l⁻¹, P < 0.0001; mean with (SD)]. However, total bioavailability did not differ between the insulins, and thus the mean residence time was significantly shorter for insulin aspart [MRT_(ins) of 149 (26) vs 217 (30) min, P < 0.0001]. Plasma glucose (PG) fell more than twice as rapidly [t_min(PG) of 94 (45) vs 226 (120) min, P < 0.0001], to a greater extent [C_min(PG) 2.1 (0.6) vs 1.4 (0.4) mmol · l⁻¹, P < 0.0001], and for a shorter duration with insulin aspart than with human insulin. Conclusion: With improved subcutaneous absorption characteristics, the insulin aspart concentration–time profile resembles physiological meal-stimulated insulin release more closely than that of unmodified human insulin. This significantly alters the pharmacodynamic response in an advantageous manner in the meal-related treatment of diabetes mellitus. Received: 26 October 1998 / Accepted in revised form: 23 January 1999     

Characterization of Solid Maltose Microneedles and their Use for Transdermal Delivery

Purpose To characterize solid maltose microneedles and assess their ability to increase transdermal drug delivery. Materials and Methods Microneedles and microchannels were characterized using methylene blue staining and scanning electron microscopy. Diffusion pattern of calcein was observed using confocal scanning laser microscopy. Transepidermal water loss (TEWL) measurements were made to study the skin barrier recovery after treatment. Uniformity in calcein uptake by the pores was characterized and percutaneous penetration of nicardipine hydrochloride (NH) was studied in vitro and in vivo across hairless rat skin. Results Microneedles were measured to be 508.46 ± 9.32 μm long with a radius of curvature of 3 μm at the tip. They penetrated the skin while creating microchannels measuring about 55.42 ± 8.66 μm in diameter. Microchannels were visualized by methylene blue staining. Pretreatment with microneedles resulted in the migration of calcein into the microchannels. TEWL increased after pretreatment and uptake of calcein by the pores was uniform as measured by the pore permeability index values. NH in vitro transport across skin increased significantly after pretreatment (flux 7.05 μg/cm²/h) as compared to the untreated skin (flux 1.72 μg/cm²/h) and the enhanced delivery was also demonstrated in vivo in hairless rats. Conclusion Maltose microneedles were characterized and shown to create microchannels in the skin, which were also characterized and shown to improve the transdermal delivery of NH.     

Mealtime glucose regulation by nateglinide in type-2 diabetes mellitus

Objectives: Pharmacodynamic effects of nateglinide, a novel antidiabetic agent, were investigated in patients with type-2 diabetes mellitus. Methods: Ten patients participated in this single-center, double-blind, crossover study. Plasma glucose and insulin levels were measured over 24 h following five 7-day treatment periods with nateglinide (30, 60, or 120 mg) or placebo given three times daily before breakfast, lunch, and dinner. A fifth treatment consisted of 120 mg nateglinide four times daily, with the fourth dose given before an evening snack. Results: Taken 10 min before meals, doses of 30–120 mg nateglinide caused dose-dependent increases in plasma insulin levels that were significantly greater than with placebo. Higher doses were more effective and had a longer duration of action than lower doses. Nateglinide was also significantly better than placebo in lowering plasma glucose levels; the 60-mg and 120-mg doses were similarly effective and superior to the 30-mg nateglinide treatment. Following the fourth 120-mg dose, the glucose-lowering effects of treatment were maintained through the night. No serious adverse events occurred during the study. There were no events of hypoglycemia and no clinically meaningful changes in safety parameters. Conclusions: Nateglinide produced rapid, short-lived, dose-related increases in plasma insulin that significantly lowered mealtime glucose excursions compared with placebo with no incidence of hypoglycemia. The decrease in mealtime glucose levels produced a significant improvement in overall 24-h glycemia. Received: 2 November 1999 / Accepted in revised form: 10 February 2000     

An open comparision of the diabetogenic effect of deflazacort and prednisone at a dosage ratio of 1.5 mg:1 mg

Objective: To compare the diabetogenic effects of deflazacort (D) versus prednisone (PN) using a dosage ratio of 1.5 mg deflazacort:1 mg prednisone. Methods: Thirty-three patients suffering from various active connective tissue or chronic inflammatory diseases were randomized to be treated with D or PN, assuming a therapeutic equipotency ratio of 1.5 mg D:1 mg PN. Neither dosage nor glucocorticoid employed were modified during the study. Patients had not received steroid treatment during the month prior to their inclusion date. Fasting glucose, glycosilated haemoglobin and fructosamine were determined before and after 1 month of treatment. Non-diabetic patients were also submitted to an oral glucose tolerance test (OGTT) at entry and after 1 month. Results were compared by univariate, and multivariate tests to correct the effects of age, body mass index and diagnosis. Results: After 1 month of treatment there were no differences between D and PN in fasting glucose, glycosilated haemoglobin, or fructosamine. OGTT performed after treatment showed similar glucose values for both treatment groups. Patients treated with D had insulin levels at min 60 of the post-treatment OGTT which were higher than those treated with PN [114.1 (62.8) mcUI · ml⁻¹ versus 73.5 (32.7) mcUI · ml⁻¹, P = 0.049], but the difference lost its statistical significance in the multivariate analysis. Conclusion: D and PN have similar effects on glucose tolerance when an equipotency ratio of 1.5 mg D:1 mg PN is employed. Previous studies employing a ratio of 1.2:1 mg may have understimated the adverse effects of D on glucose metabolism. Received: 9 July 1998 / Accepted in revised form: 30 October 1998     

Effect of dental materials on gluconeogenesis in rat kidney tubules

The effect of dental composite components triethyleneglycoldimethacrylate (TEGDMA) and hydroxyethylmethacrylate (HEMA) as well as mercuric chloride (HgCl₂) and methylmercury chloride (MeHgCl) on gluconeogenesis was investigated in isolated rat kidney tubules. From starved rats kidney tubules were prepared and isolated by digestion with collagenase. Every 10 min up to 60 min 1-ml samples were drawn from the cell suspension for quantitating the glucose content. Glucose formation in controls was 3.3 ± 0.2 nmol/mg · per min (mean ± SEM, n=21). Relative rates of glucose formation were obtained by expressing individual rates as a percentage of the corresponding control. X–Y concentration curves (effective concentration, EC) of the substances were calculated by fitting a four-parametric sigmoid function to the relative rates of glucose formation at various test concentrations. At the end of the incubation period cell viability was assessed by trypan blue exclusion. Cell viability decreased within the 60 min interval from 90 to approx. 80% (controls), <25 (HEMA), <20 (TEGDMA), <10 (MeHgCl), and <10% (HgCl₂). Values of 50% effective concentration (EC₅₀) were calculated from fitted curves. EC₅₀ values were (mmol; mean ± SEM; n=4): HEMA, 17.7 ± 2.9; TEGDMA, 1.8 ± 0.2; MeHgCl, 0.018 ± 0.0005; and HgCl₂, 0.0016 ± 0.0005. The toxic effect of HgCl₂ was ∼1000 or 10 000 higher than that of the dental composite components TEGDMA or HEMA, respectively. Received: 7 April 1999 / Accepted: 25 June 1999     

Sulphation of the heterocyclic amine 1,2,3,4-tetrahydroisoquinoline in the human liver and intestinal mucosa: interindividual variability

The sulphation rate of 1,2,3,4-tetrahydroisoquinoline (TIQ) was measured in the human liver and in the intestinal mucosa isolated from the transverse colon, ileum and duodenum. The rate (mean ± SD) of hepatic TIQ sulphation was 500 ± 174 pmol/min per mg in women (n=61) and 591 ± 201 in men (n=39; P=0.0087), varying over one order of magnitude in men and women. The sulphation rate of testosterone showed the same sex-dependent pattern and was correlated (r=0.6055; P<0.001) with that of TIQ. The frequency distribution of TIQ sulphation rate in human liver was bimodal: 70% of the population fell into the low-activity subgroup and the remaining 30% feel into the high-activity subgroup. In the colon (n=56), the rate of TIQ sulphation was 30.4 ± 15.6 pmol/min per mg and the values were similar in men and women (29.8 and 30.9 pmol/min per mg, respectively) but, varied over one order of magnitude and correlated (r=0.7231; P<0.001) with that of 4-nitrophenol. The rate of TIQ sulphation changed along the human bowel and mean (±SD) estimates for duodenum, ileum and transverse colon were 444 ± 25, 182 ± 87  and 30.4 ± 15.6 pmol/min per mg, respectively. The present results are consistent with the view that the heterocyclic amine TIQ is sulphated in the human liver and intestinal mucosa. TIQ-sulphotransferase activity varies among subjects and is mostly associated with the liver and duodenum. Received: 12 December 1996 / Accepted: 19 March 1997     

Site of nicotine absorption from a vapour inhaler – comparison with cigarette smoking

Objective: The aim of the study was to assess the site of nicotine absorption during and after use of a nicotine-vapour inhaler compared with that after cigarette smoking. Methods: Using a catheterisation technique, the nicotine plasma concentration–time profiles in arterial and jugular venous blood after using a nicotine inhaler were compared with those achieved after cigarette smoking a in seven healthy habitual smokers. Results: After use of the inhaler, arterial nicotine concentrations rose slowly to a maximum level of 5.9 ± 1.5 ng/ml at a mean time to reach peak concentration (t _max) of 9.0 ± 1.1 min, whereas jugular venous nicotine levels peaked at 25.4 ± 5.4 ng/ml at 6.7 ± 0.3 min. The concentration–time curves indicate that the absorption occurs mainly via the mucosa of the oral cavity and the pharynx, and that there is minimal absorption via the lungs. In contrast, after smoking a cigarette, arterial nicotine plasma concentrations rose quickly to a maximum level of 49.2 ± 9.7 ng/ml after 4.0 ± 0.6 min, while the maximum concentration of nicotine in the jugular vein was 22.4 ± 3.9 ng/ml after 6.4 ± 0.4 min, indicating primarily pulmonary absorption of nicotine. Conclusion: Nicotine absorption after use of the vapour inhaler occurs primarily via the mucosa of the oral cavity; the absorption occurs slowly and the arterial nicotine concentration spike, typical of cigarette smoking, is avoided. Thus, the likelihood for abuse of the nicotine inhaler is probably small. Received: 7 June 1999 / Accepted in revised form: 6 October 1999     

Inhibition of metoprolol metabolism and potentiation of its effects by paroxetine in routinely treated patients with acute myocardial infarction (AMI)

Objective To investigate the influence of paroxetine on metoprolol concentrations and its effect in patients treated for acute myocardial infarction (AMI) who are routinely given paroxetine as a co-treatment of depression. Methods We recruited 17 depressed AMI patients who received metoprolol as a routine part of their therapy (mean dose 75 ± 39 mg/day). Patients were genotyped for CYP2D6 *3, *4 and gene duplication. Metoprolol and α-hydroxy-metoprolol were analyzed in plasma 0, 2, 6 and 12 h post-dose. Heart rates (HR) at rest were registered after each sampling. Paroxetine 20 mg daily was then administered, and all measurements were repeated on day 8. Results All patients were genotypically extensive metabolizers (EMs) (nine with *1/*1 and eight with *1/*3 or *4). Following the administration of paroxetine, mean metoprolol areas under the concentration–time curve (AUC) increased (1064 ± 1213 to 4476 ± 2821 nM × h/mg per kg, P = 0.0001), while metabolite AUCs decreased (1492 ± 872 to 348 ± 279 n M × h/mg per kg, P < 0.0001), with an increase of metabolic ratios (MR) (0.9 ± 1.3 to 26 ± 29; P < 0.0001). Mean HRs were significantly lower after the study week at each time point. Mean area under the HR versus time curve (AUEC) decreased (835 ± 88 to 728 ± 84 beats × h/min; P = 0.0007). Metoprolol AUCs correlated with patients’ AUECs at the baseline (Spearman r  = −0.64, P < 0.01), but not on the eighth day of the study. A reduction of metoprolol dose was required in two patients due to excessive bradycardia and severe orthostatic hypotension. No other adverse effects of the drugs were identified. Conclusion A pronounced inhibition of metoprolol metabolism by paroxetine was observed in AMI patients, but without serious adverse effects. We suggest, however, that the metoprolol dose is controlled upon initiation and withdrawal of paroxetine.     

Safety of the novel atrial-selective K+-channel blocker AVE0118 in experimental heart failure

Congestive heart failure (CHF) is often associated with atrial fibrillation. The safety of many antiarrhythmic drugs in CHF is limited by proarrhythmic effects. We aimed to assess the safety of a novel atrial-selective K⁺-channel blocker AVE0118 in CHF compared to a selective (dofetilide) and a non-selective IKr blocker (terfenadine). For the induction of CHF, rabbits (n = 12) underwent rapid right ventricular pacing (330–380 bpm for 30 days). AVE0118 (1 mg/kg) dofetilide (0.02 mg/kg) and terfenadine (2 mg/kg) were administered in baseline (BL) and CHF. A six-lead ECG was continuously recorded digitally for 30 min after each drug administration. At BL, dofetilide and terfenadine significantly prolonged QTc interval (218 ± 30 ms vs 155 ± 8 ms, p = 0.001 and 178 ± 23 ms vs. 153 ± 12 ms, p =  0.01, respectively) while QTc intervals were constant after administration of AVE0118 (p = n.s.). In CHF, dofetilide and terfenadine caused torsades de pointes and symptomatic bradycardia, respectively, and prolonged QTc interval (178 ± 30 ms vs. 153 ± 14 ms, p = 0.02 and 157 ± 7 ms vs. 147 ± 10 ms, p = 0.02, respectively) even at reduced dosages, whereas no QTc-prolongation or arrhythmia was observed after full-dose administration of AVE0118. In conclusion, atrial-selective K⁺-channel blockade by AVE0118 appears safe in experimental CHF. H.-J. Schneider and O. Husser contributed equally.     

A medication database – a tool for detecting drug interactions in hospital

Objective: Fifty-six patients with essential hypertension were recruited to study the metabolic effects of carvedilol, a non-selective β-adrenoceptor-blocker with α₁-adrenoceptor blocking properties. Methods: The study started with a single-blind, 4–6-week placebo-treatment period followed by an open 6-month active treatment period. There was an option to increase the dose from 25 mg carvedilol to 50 mg daily after 6 weeks. Metabolic investigations were carried out at the end of the placebo period and at the end of the active treatment period. Results: The results show that during carvedilol treatment blood pressure was efficiently lowered. The increase in very low density lipoprotein triglyceride concentration was 13%. Despite this modest increase high density lipoprotein cholesterol was reduced by 11%. The metabolic clearance rate of glucose at the hyperinsulinemic clamp test (adjusted for the prevailing insulin and glucose concentrations) decreased by 17%. At the i.v. glucose tolerance test the insulin area under the curve was increased by 18% and the glucose area by 10%. Conclusion: The α₁-adrenoceptor-blocking characteristics of carvedilol probably explain the moderate changes of lipoprotein concentrations and insulin sensitivity gained compared with what is usually obtained with a non-selective β-adrenoceptor-blocker. Received: 13 February 1996 / Accepted in revised form 15 October 1996     

Measurement of furancarboxylic acid, a candidate for uremic toxin, in human serum, hair, and sweat, and analysis of pharmacological actions in vitro

3-Carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), a candidate for uremic toxin, was measured in human hair for examining a possible utility as indicator of renal dysfunction. The serum concentration of CMPF was much higher (32.3 ± 2.7 μg/ml, n=17; mean ± SEM) in uremic patients aged 40–55 years receiving hemodialysis treatment than in healthy younger subjects (3.61 ± 0.19 μg/ml, n=22), aged 18–23 years. However, the hair concentration of CMPF tended to be lower in the patients (6.8 ± 1.7 ng/10 mg hair) than in the healthy younger subjects (15.8 ± 4.5 ng/10 mg) and was significantly lower than that in the healthy age-matched subjects (22.4 ± 5.3 ng/10 mg, n=12), aged 40–47 years. Since CMPF was measurable in the sweat (4.4 ± 3.7 ng/mg) collected from six out of seven healthy subjects examined, it was suggested that the contribution of sweat to the measurement of CMPF in hair was considerable. The fact that the uremic patients undergoing hemodialysis therapy had less sweat than healthy subjects may explain the lower concentration of CMPF in the patients' hair. The pathophysiological roles of CMPF in the body were attempted to be explored by using excised guinea pig organs, and human platelets and neutrophils. CMPF showed no remarkable effects in the concentration range of ≤10⁻⁴ M except for only slight suppression of spontaneous contracture of guinea pig tenia coli at 10⁻⁴ M. As far as the organs and tissues examined in the present study are concerned, the biological activity of CMPF itself, if any, may be very weak. Precaution should be taken against the delivery of a substance through sweat to hair when a small amount of substance is attempted to be measured in hair by employing a sensitive analytical method. Received: 14 September 1999 / Accepted: 3 November 1999     

Pharmacokinetics and pharmacodynamics of propofol 6% SAZN versus propofol 1% SAZN and Diprivan-10 for short-term sedation following coronary artery bypass surgery

Objective: A new formulation of propofol 6% in Lipofundin MCT/LCT 10% (propofol 6% SAZN) has been developed in order to reduce the fat, emulsifier and volume load that is given during prolonged infusions of propofol. The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN were investigated during a short-term infusion and compared with the commercially available product propofol 1% in Intralipid 10% (Diprivan-10) and propofol 1% in Lipofundin MCT/LCT 10% (propofol 1% SAZN). Methods: In a randomised double-blind study, 24 male patients received a 5-h infusion of propofol at the rate of 1 mg/kg/h for sedation in the immediate postoperative period following coronary artery bypass surgery. Results: The average pharmacokinetic parameter estimates of clearance (Cl), volume of distribution at steady state (V_d,ss), elimination half-life (t _1/2,β) and distribution half-life (t _1/2,α) observed in the three groups were 28 ± 1.1 ml/kg/min, 1.8 ± 0.12 l/kg, 94 ± 4.1 min and 3.1 ± 0.26 min, respectively (mean ± SEM, n=24) and no significant differences were noted between the three formulations (P > 0.05). In one patient receiving propofol 6% SAZN, in two patients receiving propofol 1% SAZN and in three patients receiving Diprivan-10, the level of sedation was inadequate and additional sedative medication had to be given. In all other 18 patients, the level of sedation was adequate. The mean propofol concentration in these six inadequately sedated patients was lower than the adequately sedated patients (P=0.015). The serum triglyceride concentrations were not significantly different between the groups studied. No adverse events occurred in any of the patients. Conclusions: The pharmacokinetics, pharmacodynamics and safety characteristics of propofol 6% SAZN are in good agreement with those of the 1% formulations. Propofol 6% SAZN therefore provides a useful alternative to the commercially available 1% formulation for short-term sedation in the intensive care unit. Expected advantages in long-term sedation of the 6% over 1% formulation are the subject of an ongoing study. Received: 11 June 1999 / Accepted in revised form: 23 December 1999     

Decreased serum activity of semicarbazide-sensitive amine oxidase (SSAO) in patients treated with second generation antipsychotics: a link to impaired glucose metabolism?

Objective Although the treatment of schizophrenia with many second generation antipsychotics is known to be associated with metabolic changes, such as hyperglycemia or hypercholesterolemia, the underlying mechanisms of these adverse reactions remain unclear. In light of the recent focus on the involvement of semicarbazide-sensitive amine oxidase (SSAO) in glucose metabolism, we investigated SSAO serum activity in schizophrenic patients treated with antipsychotics with the objective of determining a possible link between SSAO and impaired glucose metabolism. Methods Blood samples were drawn from 44 schizophrenic patients (24 receiving second generation antipsychotics known to disturb glucose metabolism) on day 1 and day 5 of inpatient treatment. Forty-one healthy adults with no medical condition known to influence SSAO served as controls. Results Of the 44 schizophrenic patients, the 24 treated with second generation antipsychotics known to disturb glucose metabolism showed significantly lower SSAO serum activity [day 1 (mean ± SD): 477 ± 105 mU/L; day 5: 438 ± 86 mU/L] than the 20 patients treated with other antipsychotics not known to influence glucose metabolism (day 1: 513 ± 124 mU/L, p = 0.359; day 5: 542 ± 204 mU/L, p = 0.021) only after 5 days of treatment and compared to healthy controls (526 ± 142 mU/L, p = 0.021). No differences were observed between schizophrenic patients treated with first generation antipsychotics and the controls. Conclusion We found decreased SSAO serum activity exclusively in schizophrenic patients treated with second generation antipsychotics known to disturb glucose metabolism. In terms of the role of SSAO in glucose metabolism, the observed decrease in SSAO serum activity may be linked to metabolic changes that are known to occur in schizophrenic patients being treated with many second generation antipsychotics.     

Characterization of the Physiological Spaces and Distribution of Tolbutamide in the Perfused Rat Pancreas

Purpose To set up and validate a viable perfused rat pancreas model suitable for pharmacokinetic studies. Materials and methods We setup and conducted multiple indicator dilution studies in the single pass perfused rat pancreas. The distribution of the reference markers [^99mTc]-red blood cells (RBC), [¹⁴C]-sucrose, and [³H]-water, and tolbutamide were analysed using both non-parametric and parametric methods. Results The perfusion preparation was observed to be viable by oxygen consumption, outflow perfusate pH, lactate release and insulin release in response to glucose. Parametric analysis of the outflow profiles suggested that the transport of water and tolbutamide from the vascular space was permeability limited. Parametric and nonparametric estimates of V _d for RBC and sucrose were similar and were 0.14 ± 0.01, 0.15 ± 0.005 and 0.35 ± 0.01 ml/g. The parametric estimate for water, 1.04 ± 0.05 ml/g was greater than the nonparametric estimate, 0.89 ± 0.02 ml/g. The multiple indicator dilution method V _d of tolbutamide of 0.75 ± 0.08 ml/g was similar to the reported value of 0.73 ± 0.04 ml/g estimated by tissue partitioning studies. Conclusions A viable single pass pancreas perfusion model was established and applied to define distribution spaces of reference markers and the distribution kinetics of tolbutamide.