Porcine carotid vascular effects of eletriptan (UK-116,044): a new 5-HT1B/1D receptor agonist with anti-migraine activity

It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine. Indeed, a number of acutely acting anti-migraine drugs, including the ergot alkaloids and sumatriptan, constrict porcine carotid arteriovenous anastomoses. In this study, using pentobarbital anaesthetised pigs, we investigated the effects of eletriptan, a close structural analogue of sumatriptan, on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient (capillary) fractions. Eletriptan (10, 30, 100, 300 and 1000 μg kg^–1, i.v.) decreased the total carotid blood flow, exclusively by decreasing cephalic arteriovenous anastomotic blood flow; nutrient blood flow, particularly to the ear, skin and fat, was significantly increased. The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50% (ED ₅₀) were, respectively, 117±21 μg kg^–1 (251±45 nmol kg^–1) and 184±42 μg kg^–1 (396±91 nmol kg^–1); the highest dose caused reductions of 84±3% and 77±4%, respectively. The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective 5-HT_1B/1D receptor antagonist GR127935 (0.5 mg kg^–1). On the basis of these results, we conclude that (1) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by 5-HT_1B/1D receptors, and (2) eletriptan should be effective in aborting migraine headache. Clinical studies have already demonstrated its therapeutic action in migraine patients. Received: 9 February 1998 / Accepted: 28 March 1998     

Changes in systemic and regional haemodynamics during 5-HT7 receptor-mediated depressor responses in rats

The 5-hydroxytryptamine (5-HT)-induced late depressor response in rats is mainly mediated by vascular 5-HT₇ receptors. The present study was devoted to determining the systemic and regional haemodynamic changes during this response, with particular emphasis on localising vascular beds that may contribute to the increase in total systemic vascular conductance. In vagosympathectomised, pentobarbital-anaesthetised rats pretreated with the 5-HT₂ receptor antagonist ritanserin (50 μg kg^–1, i.v.), 5-HT (1, 3 and 10 μg kg^–1 min^–1 during 10 min; i.v.) produced a dose-dependent decrease in mean arterial blood pressure by up to 46±3%. This decrease was accompanied by increases in systemic vascular conductance by up to 83±15%; cardiac output was unaffected. 5-HT increased regional vascular conductance in skeletal muscle, carcass, mesentery/pancreas and adrenals by up to 740±141%, 117±18%, 135±26% and 88±22%, respectively, but decreased ‘lung’ (mainly arteriovenous anastomotic) conductance by up to 81±2%. Pretreatment with R(+)lisuride (100 μg kg^–1, i.v.) abolished all 5-HT-induced systemic and regional haemodynamic effects. In contrast, i.v. pretreatment with S(–)lisuride (100 μg kg^–1) or GR127935 (300 μg kg^–1) did not affect the 5-HT-induced systemic haemodynamic changes. The above results suggest that hypotension induced via 5-HT₇ receptor activation was exclusively caused by vasodilatation of the systemic vasculature, confined to skeletal muscle, carcass, mesentery/pancreas and adrenal vascular beds. Furthermore, this study shows that blockade of vaso-relaxant 5-HT₇ receptors by lisuride is stereoselective. Received: 10 November 1998 / Accepted: 13 January 1999     

Nature of 5HT1like receptors mediating depressor responses in vagosympathectomized rats; close resemblance to the cloned 5ht7 receptor

It has been suggested that the late hypotensive response to serotonin (5hydroxytryptamine; 5HT) in vagosympathectomized rats is mediated by ‘5HT₁like’ receptors since this effect is mimicked by 5carboxamidotryptamine (5CT), is not modified by cyproheptadine, ketanserin or MDL72222, but it is blocked by methysergide. The present study was set out to reanalyze this suggestion in terms of the classification schemes proposed in 1994 and 1996 by the NCIUPHAR subcommittee on the classification and nomenclature of 5HT receptors. I.v. bolus injections of 5CT (0.010.3μg·kg¹), 5HT (130μg·kg¹) and 5methoxytryptamine (5MeOT; 130μg·kg¹) produced dosedependent hypotensive responses with a rank order of agonist potency: 5CT >> 5HT ≥ 5methoxytryptamine with sumatriptan (301000μg·kg¹) inactive. The depressor responses to 5HT and 5CT were not attenuated by i.v. GR127935 (3003000μg·kg¹) or equivalent volumes of saline. In contrast, lisuride, methiothepin, mesulergine, metergoline and clozapine dose-dependently antagonized the responses to 5HT and 5CT; the rank order of apparent pA₂ values against 5HT and 5CT, respectively, was: lisuride (7.7; 7.8) > methiothepin (6.8; 7.0) ≥ mesulergine (6.4; 6.6) > clozapine (5.7; 5.8); metergoline displayed variable potencies (5.6; 6.4). Except for lisuride, which also affected isoprenalineinduced hypotension, the antagonism by the other drugs was selective. Based upon the above rank order of agonist potency, the blockade by a series of drugs showing high affinity for the cloned 5ht₇ receptor and the lack of blockade by GR127935, our results indicate that the 5HT receptor mediating hypotension in vagosympathectomized rats is operationally similar to other putative 5ht₇ receptors mediating vascular and nonvascular responses (e.g. relaxation of the rabbit femoral vein, canine coronary and external carotid arteries and guineapig ileum as well as feline tachycardia). Received: 11 February 1997 / Accepted: 1 April 1997     

Effects of S20749, a Close Analogue of Sumatriptan,on Porcine Carotid Haemodynamics and Human Isolated Coronary Artery

Abstract: Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT_1D receptor agonists, have the ability to constrict porcine arteriovenous anastomoses. Sumatriptan also constricts the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of S20749 (1-[2-(dimethylamino)ethyl]-naphthalene-7-methylsulfonamide), a close analogue of sumatriptan. S20749 (30, 100 , 300 and 1000 μg · kg^?1) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow was moderately increased. These changes were statistically significant with the highest two doses. S20749 moderately constricted the human isolated coronary artery (pD₂: ≤4.5; E_max: >11% of the contraction to 100 mM K⁺). The above results suggest that S20749 should be able to abort migraine headaches in patients.     

Dilatory effects of phosphodiesterase inhibitors on human hand veins in vivo

Objective: To compare the venodilator potencies of the phosphodiesterase (PDE) III inhibitors amrinone and enoximone with the unspecific PDE inhibitors theophylline and pentoxifylline in human hand veins in vivo. Methods: Eighteen healthy nonsmokers (16 men and two women) were studied using the dorsal hand vein technique. After preconstriction with the selective α₁-adrenergic-receptor agonist phenylephrine dose–response curves were constructed for amrinone (1–270 μg · min⁻¹), enoximone (1–270 μg · min⁻¹), theophylline (5–1500 μg · min⁻¹) and pentoxifylline (2–877 μg · min⁻¹) in a random order on separate occasions. Due to limitation in the maximum dose infused in order to avoid systemic effects, full dose–response curves could not be constructed for pentoxifylline. In this case, the individual dose of pentoxifylline and theophylline producing 50% venodilation were compared. Results: All PDE inhibitors induced dose-dependent venodilation. The value of maximum venodilation was the same for amrinone, enoximone and theophylline. The infusion rate needed to induce 50% of maximum venodilation (ED₅₀) was not significantly different for amrinone (geometric mean, 8.8 μg · min⁻¹) and enoximone (14.2 μg · min⁻¹), whereas the ED₅₀ of theophylline (84.0 μg · min⁻¹) was significantly higher than either amrinone or enoximone. The dose necessary to dilate the vein to 50% the maximum dilation (as determined during sodium chloride infusion) was significantly higher for pentoxifylline than for theophylline (409 vs 71 μg · min⁻¹). Conclusions: These findings demonstrate that enoximone and amrinone have similar venodilatory potency which is six times higher than that of theophylline. The least potent vasodilator in this study was pentoxifylline. Received: 16 September 1997 / Accepted in revised form: 4 December 1997     

Penetration of ciprofloxacin, norfloxacin and ofloxacin into the aqueous humour of patients by different topical application modes

Objectives: A prospective study was undertaken to determine the transcorneal penetration of three topically applied fluoroquinolones into aqueous humour. Methods: Two hundred and twenty-four patients undergoing cataract extraction received 0.3% ciprofloxacin, norfloxacin or ofloxacin eye drops by two different administration modes with different frequencies and intervals of application. At the beginning of cataract extraction (0.5–3 h after the last drop), 50–100 μl aqueous fluid was aspirated from the anterior chamber and immediately stored at −80 °C. Antibiotic concentrations were measured using high-performance liquid chromatography. Results: Generally, topical ofloxacin and ciprofloxacin yielded aqueous humour levels higher than topical norfloxacin. The highest concentrations of all tested fluoroquinolones were measured after using an application mode, in which one drop was given every 15 min between 0600 hours and 0800 hours, prior to operation. When applied by this mode, ciprofloxacin achieved a mean aqueous level of 0.380 (±0.328) μg · ml⁻¹ (range 0.033–1.388 μg · ml⁻¹), norfloxacin 0.182 (0.118) μg · ml⁻¹ (range 0.038–0.480 μg · ml⁻¹) and ofloxacin 0.564 (0.372) μg · ml⁻¹ (range 0.064–1.455 μg · ml⁻¹). These mean concentrations were above the minimum inhibitory concentration (MIC₉₀), concentrations required for inhibition of 90% of pathogen strains in vitro of gram-negative bacteria, such as Proteus mirabilis and Escherichia coli. Therapeutic values above the MIC₉₀ of Staphylococcus epidermidis, the pathogen causing eye infections most frequently, were reached by 67.5% of patients after ofloxacin and by 41% after ciprofloxacin, but never after norfloxacin treatment. Conclusion: Of the currently available topical fluoroquinolones, ofloxacin achieved the highest aqueous humour concentration. This fluoroquinolone may be an useful ophthalmic agent for topical antibacterial management, but it does not seem to be prophylactically effective against Streptococcus pneumoniae or Pseudomonas aeruginosa. Received: 22 April 1997 / Accepted: 8 June 1997     

Pharmacokinetic and pharmacodynamic studies following single and multiple doses of rolafagrel,a novel inhibitor of thromboxane synthase,in normal volunteers

The pharmacokinetics and pharmacodynamics of rolafagrel (FCE 22178), a novel thromboxane synthase inhibitor, were evaluated after single and multiple oral doses in eight healthy volunteers. After a single dose (400 mg), the drug was absorbed rapidly, peak plasma concentrations being attained within 2 h in all subjects. Elimination followed a biphasic course, with a rapid initial decline followed after 12–24 h by a late phase with a terminal half-life of about 10h. About 100% of the administered dose could be recovered in urine within 72 h, mostly in conjugated form. During multiple dosing (400 mg t.i.d. for 5 days), steady-state conditions were approached on day 2 and AUC values over a dosing interval were similar to those observed after a single dose (72.3 vs 76.3 μg·ml⁻¹·h). Pharmacokinetic parameters calculated after multiple doses were similar to those observed after a single dose (C_max: 20.1 vs 18.2 μg·ml⁻¹; t_max: 1.2 vs 1.1 h; terminal half-life: 10.9 vs 11.4 h; CL: 85.2 vs 70.4 ml·h⁻¹;V: 1.23 vs 1.241·kg⁻¹). Platelet generation of thromboxane B₂, the stable breakdown product of thromboxane A₂, was inhibited by 85% at a plasma rolafagrel concentration of about 4μg·ml⁻¹, and only a small increase in inhibition was observed at higher concentrations.     

Potassium channels are involved in testosterone-induced vasorelaxation of human umbilical artery

Recent studies have shown that testosterone induces relaxation of different arteries, although the mechanism of this action is still under debate. We investigated the involvement of potassium channels in this mechanism. Using standard organ bath techniques, rings of human umbilical arteries (HUA) without endothelium were contracted by serotonin (5-HT, 1 μM), histamine (10 μM) and potassium chloride (KCl, 30 and 60 mM), and the vasorelaxant effect of testosterone was analysed. Testosterone (100 μM) relaxed human umbilical arteries contracted with 5-HT (30.1 ± 3.2%), histamine (55.1 ± 2.6%), KCl 30 mM (52.9 ± 8.3%) and KCl 60 mM (54.8 ± 6.3%). Flutamide (10 μM), an inhibitor of classical intracellular testosterone receptor, and glibenclamide, an ATP-sensitive potassium-channels (K_ATP) inhibitor, did not influence the testosterone relaxant effect. 4-aminopyridine, a voltage-sensitive potassium-channels (Kv) inhibitor, decreased the effect of testosterone on histamine- and 5-HT-contracted arteries. Tetraethylammonium (TEA), which inhibits Kv channels and large-conductance Ca²⁺-activated potassium channels (BK_Ca), decreased the effect of testosterone on KCl (60 mM)-contracted and 5-HT-contracted HUA. In conclusion, testosterone induces relaxation of HUA, and this effect does not appear to be mediated via a classic intracellular testosterone receptor-dependent mechanism. Our results suggest that this relaxation is partially mediated by activation of BK_Ca and K_V channels. The involvement of these two channels in testosterone-relaxant mechanism is dependent on the pathways activated by the contractile agent used.     

Pharmacokinetics of intravenous ATP in cancer patients

Objective: To characterise the pharmacokinetics of adenosine 5′-triphosphate (ATP) in patients with lung cancer after i.v. administration of different ATP dosages. Methods: Twenty-eight patients received a total of 176 i.v. ATP courses of 30 h. Fifty-two infusions were given as low-dose infusions of 25–40 μg kg⁻¹ min⁻¹, 47 as middle-dose infusions of 45–60 μg kg⁻¹ min⁻¹ and 77 as high-dose infusions of 65–75 μg kg⁻¹ min⁻¹ ATP. Kinetic data of ATP concentrations in erythrocytes were available from 124 ATP courses. Results are expressed as mean ± SEM. Results: Most ATP courses in cancer patients were without side effects (64%), and side effects occurring in the remaining courses were mild and transient, resolving within minutes after decreasing the infusion rate. Baseline ATP concentration in erythrocytes was 1554 ± 51 μmol l⁻¹. ATP plateau levels at 24 h were significantly increased by 53 ± 3, 56 ± 3 and 69 ± 2% after low-dose, middle-dose and high-dose ATP infusions, respectively. At the same time, significant increases in plasma uric acid concentrations were observed: 0.06 ± 0.01, 0.11 ± 0.01 and 0.16 ± 0.01 mmol l⁻¹, respectively. The mean half-time for disappearance of ATP from erythrocytes, measured in five patients, was 5.9 ± 0.5 h. Conclusions: During constant i.v. infusion of ATP in lung cancer patients, ATP is taken up by erythrocytes and reaches dose-dependent plateau levels 50–70% above basal concentrations at approximately 24 h. Received: 7 July 1999 / Accepted in revised form: 30 December 1999     

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     

Bronchodilator and anti-inflammatory activities of SCA40: Studies in human isolated bronchus, human eosinophils, and in the guinea-pig in vivo

There is currently interest in the use of inhibitors of cyclic nucleotide phosphodiesterases (PDE) as potential anti-asthma agents. In this study we examined the effects of SCA40 (6-bromo-8-methylaminoimidazol[1,2-a] pyrazine-2-carbonitrile), a preferential inhibitor of PDE 3 also endowed with PDE 4 and 5 inhibitory activities, on isolated bronchus and eosinophil functions and in an animal model of asthma. SCA40 (1 nM–0.1 mM) produced concentration-dependent inhibition of spontaneous and stimulated tone of human isolated bronchus and reached a maximal relaxation similar to that of theophylline (3 mM). The potency (–log EC₅₀ values) of SCA40 against spontaneous tone (6.52 ± 0.10) was greater than against tone raised by equieffective concentrations (∼ 70%) of histamine (5.76 ± 0.06), leukotriene C₄ (5.44 ± 0.11), and acetylcholine (4.98 ± 0.09). In the presence of cytochalasin B, the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 0.5 μM) induced leukotriene C₄ production in human eosinophils isolated in discontinuous metrizamide gradients. The production of leukotriene C₄ was inhibited by SCA40 in a concentration-related fashion (–log IC₅₀ = 6.04 ± 0.20; n = 6). Rolipram, a selective PDE 4 inhibitor, was also effective (–log IC₅₀ = 7.29 ± 0.32) but the selective PDE 3 inhibitor SKF94120 was scarcely effective (< 10% inhibition for 10 μM). In ovalbumin sensitized guinea-pigs, SCA40 (1 mg kg^–1, i.p.) given 30 min before antigen challenge significantly inhibited the acute bronchoconstriction produced by aerosol antigen (5 mg ml^–1, 30 s) (antigen response was 185 ± 13 and 91 ± 21 cmH₂O l^–1 s^–1 in control and SCA40-treated animals, respectively, P < 0.05). Pretreatment with SCA40 (1 mg kg^–1, i.p., 30 min pre- and 3 h post-antigen exposure) prevented airway hyperreactivity to histamine which developed 24 h after exposure of conscious guinea-pigs to aerosol antigen. Eosinophil lung accumulation that accompanied airway hyperreactivity was also inhibited by SCA40 (from 6.15 ± 0.86 in control to 1.27 ± 0.27 in treated animals; expressed as eosinophils × 10⁶; P < 0.05). SCA40 (1 mg kg^–1, i.p.) also inhibited the microvascular leakage produced after inhaled antigen (5 mg ml^–1, 30 s) at all airway levels. The haemodynamic effects of SCA40 (1 mg kg^–1, i.p.) consisted of a rapid decrease (peak at 5 min) in mean arterial blood pressure (–39.4 ± 2.4%) and tracheal mucosal blood flow (–13.5 ± 2.0%) that slowly recovered with time. These data support previous work showing that PDE inhibition results in anti-spasmogenic and anti-inflammatory effects. SCA40 was effective in vitro and in vivo and these effects are probably related to its activity as a mixed PDE inhibitor. Received: 13 March 1997 / Accepted: 28 July 1997     

Inhibition of CYP2C9 by selective serotonin reuptake inhibitors: in vitro studies with tolbutamide and (S)-warfarin using human liver microsomes

Objective: To investigate the in vitro potential of selective serotonin reuptake inhibitors (SSRIs) to inhibit two CYP2C9-catalysed reactions, tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Methods: The formation of 4-hydroxytolbutamide from tolbutamide and that of 7-hydroxywarfarin from (S)-warfarin as a function of different concentrations of SSRIs and some of their metabolites was studied in microsomes from three human livers. Results: Both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation followed one enzyme Michaelis-Menten kinetics. Kinetic analysis of 4-hydroxytolbutamide formation yielded a mean apparent Michaelis-Menten constant (K_m) of 133 μM and a mean apparent maximal velocity (V_max) of 248 pmol · min⁻¹ · mg⁻¹; formation of 7-hydroxywarfarin yielded a mean K_m of 3.7 μM and a mean V_max of 10.5 pmol · min⁻¹ ·  mg⁻¹. Amongst the SSRIs and some of their metabolites tested, only fluvoxamine markedly inhibited both reactions. The average computed inhibition constant (K_i) values and ranges of fluvoxamine when tolbutamide and (S)-warfarin were used as substrate, were 13.3 (6.4–17.3) μM and 13.0 (8.4–18.7) μM, respectively. The average K_i value of fluoxetine for (S)-warfarin 7-hydroxylation was 87.0 (57.0–125) μM. Conclusion: Amongst the SSRIs tested, fluvoxamine was shown to be the most potent inhibitor of both tolbutamide 4-methylhydroxylation and (S)-warfarin 7-hydroxylation. Fluoxetine, norfluoxetine, paroxetine, sertraline, desmethylsertraline, citalopram, desmethylcitalopram had little or no effect on CYP2C9 activity in vitro. This is consistent with in vivo data indicating that amongst the SSRIs, fluvoxamine has the greatest potential for inhibiting CYP2C9-mediated drug metabolism. Received: 20 July 1998 / Accepted in revised form: 6 October 1998     

Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries

Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK₁ receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor N ^ω-nitro-l-arginine methyl ester HCl (l-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K⁺ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM) + apamin (0.1 μM) and iberiotoxin (0.5 μM) + apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK₁, NO, vanilloid receptors, voltage-sensitive calcium channels, K⁺ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.     

Disprocynium24 induces a dopamine-independent, eukaliuric diuresis and natriuresis in the anaesthetized rat

In the anaesthetized rat, intravenous administration of the isocyanine 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) at doses up to 600 μg/kg resulted in marked diuresis and natriuresis without affecting urinary potassium excretion. Fractional sodium excretion was increased over 10-fold indicating a high ceiling-diuretic action. The effects of disprocynium24 on renal function were accompanied by a dose-dependent reduction in heart rate (HR) and mean arterial blood pressure (MAP). Acute administration of 600 μg/kg disprocynium24 decreased MAP by 25% and, in addition, caused a fall in glomerular filtration rate (GFR). Since i) disprocynium24 has been shown to interfere with urinary dopamine excretion (U_DAV) and ii) dopamine has been implicated with the regulation of renal sodium excretion, we hypothesized that the effects of disprocynium24 might be mediated by its effects on renal dopamine handling. The following findings, however, argue against this hypothesis. First, administration of disprocynium24 in single doses up to 600 μg/kg caused a diuresis and natriuresis, but did not significantly affect U_DAV. Second, neither the systemic nor the renal response to disprocynium24 were markedly altered by pretreatment with the dopamine D₁- or D₂-receptor blockers SCH23390 (10 μg · kg^–1· min^–1) or S(-)sulpiride (15 μg · kg^–1· min^–1), respectively. Received: 25 August 1997 / Accepted: 23 September 1997     

Adrenocortical activity with repeated administration of one-daily inhaled fluticasone propionate and budesonide in asthmatic adults

Objective: The aim of this study was to evaluate the steady-state effects of once-daily inhaled fluticasone propionate (FP) and budesonide (BUD) on adrenocortical activity in asthmatic patients. Methods: Ten asthmatic patients with a mean age of 31.2 years, a mean forced expiratory volume in 1 s (FEV₁) of 91% predicted and a forced mid-expiratory flow (FEF_25–75) of 62.3% predicted were studied in a single-blind randomised crossover design comparing placebo (PL), FP (375 μg per day and 750 μg per day) and BUD (400 μg per day and 800 μg per day) all given once daily for 4 days at each dose via a pressurised metered dose inhaler (pMDI) at 0800 hours. After 4 days of treatment, plasma cortisol was measured at 0800 hours (24 h after the last dose) and a 10-h overnight urine collection was taken, 14 h after the last dose (2200–0800 hours) for analysis of cortisol and creatinine excretion. Results: Plasma cortisol levels (nmol · l⁻¹, as geometric mean) at 0800 hours demonstrated a significant difference between the highest doses of FP and BUD (424.1 vs 510.3 nmol · l⁻¹, respectively) but not between the low doses (506.8 vs 514.9 nmol · l⁻¹; PL 532.2 nmol · l⁻¹). For the highest dose FP (750 μg) this equated to 20% suppression of 0800 hours plasma cortisol. Likewise, for overnight urinary cortisol output (nmol · 10 h⁻¹, as geometric mean), there was a significant difference at the high doses of FP and BUD (25.5 vs 38.2 nmol · 10 h⁻¹), but not at the low doses 31.3 vs 34.8 nmol · 10 h⁻¹; PL 32.0 nmol · 10 h⁻¹. For the overnight urinary cortisol/creatinine ratio (nmol · mmol⁻¹, as geometric mean) there was a similar trend; 4.5 vs 6.1 nmol · mmol⁻¹ for high dose and 5.6 vs 6.3 nmol · mmol⁻¹ for low dose; PL 5.9 nmol · mmol⁻¹. Conclusion: Repeated doses of FP 750 μg once daily caused greater adrenal suppression than BUD 800 μg once daily, when comparing effects on plasma cortisol levels at 0800 hours, 24 h after the last dose, as well as effects on overnight urinary cortisol output. Neither FP 375 μg once daily nor BUD 400 μg once daily produced detectable adrenal suppression. Received: 29 April 1997 / Accepted in revised form: 5 July 1997     

Pharmacokinetics and tolerability of oral iloprost in thromboangiitis obliterans patients

Objective: Iloprost is a potent PGI₂ mimetic, which has been shown to be therapeutically effective in several vascular disorders. Due to its rapid clearance from the central compartment, iloprost is administered mainly by i.v. infusion, which limits its use to hospitalized patients. In order to improve pharmacotherapeutic use of this PGI₂ mimetic, an oral extended-release (ER) dosage form has been developed, which should mimic plasma level profiles as observed after i.v. infusion and serve as a therapeutic equivalent. Methods: This trial was performed to investigate the tolerability and pharmacokinetics of iloprost administered perorally, compared with i.v. infusion, in 12 patients suffering from thromboangiitis obliterans (TAO). A dose titration was carried out for 1 week with i.v. iloprost, followed by a p.o. titration and treatment phase of 3 weeks' duration. Pharmacokinetics was investigated at the individually tolerated dose levels; i.e., on days 5–7 (i.v. infusion at 2, 2.5 and 3 ng · kg⁻¹ · min⁻¹), and twice during p.o. treatment after b.i.d. administration of 50, 100, 150, 200 or 300 μg. Results: Individual tolerability of iloprost varied: 7 patients out of 12 tolerated the maximum i.v. dose of 3 ng · kg⁻¹ · min⁻¹; six tolerated the maximum oral dose of 600 μg. No patients withdrew from the study due to adverse events. Flush and headache were the most common adverse events and seemed to be related to the study drug. After i.v. infusion of iloprost, dose-normalized (3 ng · kg⁻¹ · min⁻¹), steady-state plasma levels were 260 pg · ml⁻¹. Terminal half-life was 0.57 h. Total clearance ranged from 8 to 17 ml · min⁻¹ · kg⁻¹. Peroral administration of the ER formulation resulted in dose-dependent C_max and AUC values. AUC values of the first and second daily dose interval, i.e., 0–5 h and 5–11 h after first dosing, were almost identical. Absolute bioavailability was 24%, with the exception of two patients who tolerated only 50 μg b.i.d. and exhibited a bioavailability of approx. 60%. The AUC values observed in weeks 2 and 4 were identical, demonstrating low day-to-day variability of iloprost plasma level profiles in TAO patients. Conclusion: Based upon pharmacokinetic data, the ER formulation provides an equivalent to the i.v. infusion of iloprost and broadens the range of therapy to non-hospitalized patients. The availability of capsules with 50 and 100 μg iloprost enables individual dose titration and pharmacotherapy. Beneficial effects, as observed with i.v. iloprost in TAO patients, should therefore be achievable by peroral pharmacotherapy using the new ER formulation. Received: 18 July 1996 / Accepted in revised form: 2 April 1997     

Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects

Objective: The pharmacokinetics of a single i.v. dose of the new racemic β-adrenoceptor-blocker nebivolol [0.073 mg base · kg^–1 ideal body weight (IBW)] was studied in 9 obese (157% IBW) and 9 non-obese healthy volunteers (98% IBW). Each group contained 4 men and 5 women, aged 32 years, including one poor hydroxylator (dextrometorphan test). Methods: The cardiovascular effects of nebivolol are significant decreases in systolic and diastolic blood pressure, heart rate and cardiac output, which last up to 4–5 h. The plasma concentrations of the separate d- and l- enantiomers of nebivolol, with and without hydroxylated metabolite, were measured by radioimmunoassay and the unchanged racemate by high-pressure liquid chromatography (HPLC). The pharmacokinetic parameters for each form were calculated separately. Results: The main pharmacokinetic parameters of unchanged nebivolol in extensive metabolizers were (controls): distribution volume at steady state (V_ss) 673 l; volume corrected by real body weight (V_ss · kg^–1) 11.2 l ·  kg^–1; total clearance (CL) 51.6 h^–1; and terminal half-life (t_1/2) 10.3 h. The V_ss (898 l) and CL (71.6 l · h^–1) were significantly higher in obese patients. But V_ss · kg^–1 (9.4 l · kg^–1) and t_1/2 (10.0 h) were not significantly different from those in controls. The CL was clearly reduced (15–18 l · h^–1) and the t_1/2 prolonged (32–34 h) in poor hydroxylators, in both control and obese subjects. The pharmacokinetic parameters of the separate unchanged enantiomers were similar to those of the racemate in both groups. The pharmacokinetics of l-nebivolol were more influenced by the hydroxylation phenotype than those of d-nebivolol. The trend of the results for the sum of each enantiomer plus its metabolite, was similar to those for the unchanged form. Conclusion: The distribution of nebivolol in the adipose tissue in obese subjects is limited, despite its high lipophilicity. The differences between obese and non-obese subjects were not clinically relevant. Received: 22 December 1995 / Accepted in revised form: 5 June 1996     

Meta-analytic review of the clinical effectiveness of oral deferiprone (L1)

Objective: To summarize efficacy and effectiveness in iron overloaded patients treated with the orally active iron chelator deferiprone also known as L₁ or, using meta-analysis of the literature. Methods: We reviewed the literature, searching Medline and Embase databases, as well as reviews and other literature on the topic. Inclusion criteria were: original clinical trials reporting results for serum ferritin concentration (SF), hepatic iron concentration or urinary iron excretion (UIE). Efficacy data had to have been reported after ≥3 months of treatment. Data were combined using a random effects model (Cochrane) modified for use with single groups to produce a point estimate and a 95% confidence interval. To summarize the clinical effectiveness, overall proportion of patients where deferiprone was able to reduce serum ferritin was calculated. We also examined average (mg · l⁻¹) serum ferritin levels over the reported time (mean) and absolute decrease from the baseline after therapy. To summarize efficacy, success was defined as the proportion of patients who achieved UIE of 25 mg per day or 0.5 mg · kg⁻¹ · day⁻¹, which equals the average amount received from monthly blood transfusions. We also calculated the overall average level (mg per day) of UIE over the reported time of therapy (mean). As part of a sensitivity analysis, data were analyzed for two ranges of deferiprone dosage: ≤50 mg · kg⁻¹ · day⁻¹ and ≥75 mg · kg⁻¹ · day⁻¹. Results: Of 83 identified references, nine clinical trials met our inclusion criteria, providing data for 129 iron overloaded patients. After a mean of 16 months of therapy (range 6.4–36 months) with 66.4 mg · kg⁻¹ · day⁻¹ (mean) of deferiprone, 75.5% of highly iron overloaded patients had a decrease in serum ferritin from baseline. The average drop in serum ferritin of 0.8 mg · l⁻¹ was 23.5% from baseline. The overall average UIE for therapy was 28.8 mg per day in patients receiving ≥75 mg · kg⁻¹ · day⁻¹ over 8.5 months of therapy. At the same dosage, more than half of the patients (51.8%) achieved negative iron balance. When studies with patients receiving lower dosage (≤50 mg · kg⁻¹ · day⁻¹) were included, the success rate was 45.1%. Conclusion: Overall, deferiprone has clinical efficacy in achieving negative iron balance and reducing body iron burden in highly iron overloaded patients. After an average of 16 months of deferiprone in doses ≥75 mg · kg⁻¹ · day⁻¹, most patients had a decrease in ferritine concentration. Received: 1 July 1998 / Accepted in revised form: 17 November 1998     

Cardiovascular effects of different infusion rates of sufentanil in patients undergoing coronary surgery

   Objective: Pharmacokinetics and haemodynamic effects of a total dose of 15 μg · kg⁻¹ sufentanil, an opioid anaesthetic agent, were studied in patients undergoing aortocoronary bypass surgery at three infusion rates of 30 (group I), 5 (group II), and 2 (group III) μg · kg⁻¹ · min⁻¹, respectively. Results: Plasma concentrations of sufentanil could be optimally characterized by a linear biexponential pharmacokinetic model. Non-compartmental analyses indicated that there was no significant difference in the values of clearance (11.6, 13.3, 14.3 ml · min⁻¹ · kg⁻¹), steady-state volume of distribution (0.220, 0.255 and 0.331 l · kg⁻¹) and mean residence time (18.8, 13.3 and 14.3 min) among the groups. The observed mean C_max values of 421 (group I), 125 (group II), and 53 (group III) ng · ml⁻¹ and observed mean AUC values from 0 to 3 min were all consistent with the dosing regimens. There were large inter-individual variations in haemodynamic response. Compared to plasma data, a delay in haemodynamic effects was found. Times to reach peak haemodynamic effect ranged from 4.3 to 4.9 min for group I, from 4.6 to 6.1 min for group II, and from 9.9 to 11.3 for group III. Except heart rate, peak haemodynamic effects in these study patients generally ranged from 20.9% to 35.2%. Significant reductions in the area under the effect-time profiles of mean arterial blood pressure and systemic vascular resistance were observed in group II and group III, but not in group I. Significant reductions in the area under the effect-time profiles of left ventricular stroke work index were observed in group III only. No effect on heart rate was found in any group. Conclusion: Our findings suggested that a slower infusion rate of sufentanil at a dose of 15 μg · kg⁻¹ tends to give a greater reduction in mean arterial blood pressure, systemic vascular resistance, and left ventricular stroke work index than does a faster infusion rate. Received: 23 August 1995 / Accepted in revised form: 19 August 1996     

Pharmacokinetics of oxypolygelatine in healthy volunteers

Objective/methods: The pharmacokinetics of the plasma substitute oxypolygelatine (OPG) were studied in 12 healthy volunteers after single-dose administration of 27 ml · kg⁻¹ body weight, with a maximum of 2000 ml. OPG was determined in plasma and urine over 48 h after the infusion. Peak plasma OPG concentrations at the end of the infusion were determined to 4.600 (623) μg · ml⁻¹, the area under the plasma concentration/time curve (AUC_0∞) was calculated to 70.135 (15.861) μg · h · ml⁻¹. Results: The model-independently calculated volume of distribution came to 23.1 (4.8) l with a clearance total is (Cl_tot) of 24.6 (6.8) ml · min⁻¹. The initial half-life according to a three-compartment model came to 0.3 (0.2) h, followed by a distribution half-life of 3.1 (2.6) h and a terminal elimination half-life of 13.4 (2.2) h. Cumulative urinary excretion of OPG was 64% after 48 h. Conclusion: This low recovery rate may be explained by the distribution of OPG into the extravascular space and subsequent degradation in tissue sites. Received: 9 June 1998 / Accepted in revised form: 23 November 1998