The airway effects of stopping regular oral theophylline in patients with asthma

Aims We investigated whether the deterioration in asthma control reported following cessation of theophylline was due to tolerance to theophylline.
Methods Eighteen subjects with mild stable asthma were given oral theophylline 10  mg  kg⁻¹ day⁻¹ or placebo for 2 weeks in a double-blind crossover study. FEV₁ and PD₂₀ histamine were measured before and 8  h after the first dose of treatment and 8, 32 and 56  h after the final dose. PD₂₀ AMP was measured before treatment and 9  h after the final dose.
Results Six patients did not tolerate theophylline. In the other 12 subjects there were no differences between treatments in daily PEF, symptom scores, rescue bronchodilator use, PD₂₀ histamine or FEV₁ up to 8  h post treatment. Following withdrawal of theophylline there were significantly lower values for mean FEV₁ (mean difference 0.15  l, 95% CI 0.03, 026) and PD₂₀ AMP compared to placebo but no difference in other end points.
Conclusions The small rebound deterioration in lung function following regular treatment with therapeutic doses of oral theophylline is consistent with the development of tolerance.     

Adverse effects of a single dose of (+)-sotalol in patients with mild stable asthma

Aims To investigate the effect of (+)-sotalol, which is not thought to possess clinically significant β-adrenoceptor blocking activity, on airway responsiveness in subjects with mild asthma.
Methods A placebo controlled, double-blind, single dose, cross over study, evaluating the effects of oral (+)-sotalol 300  mg and oral (±)-sotalol 240  mg, on airway responsiveness, FEV₁, and heart rate in 18 asthmatic volunteers with quantifiable levels of airway responsiveness.
Results Compared with placebo, (+)-sotalol induced a significant increase in airway responsiveness, and a significant decrease in FEV₁, but there was no significant change in heart rate. Following (±)-sotalol there was no significant effect on airway responsiveness, but there were significant decreases in FEV₁ and heart rate. In one subject both (+)-sotalol and (±)-sotalol provoked a 49% decrement in FEV₁, and in another there were decrements of 20% and 18%, respectively.
Conclusions Despite theoretical considerations, it cannot be assumed that (+)-sotalol is safe in patients with asthma.     

Benazepril, an angiotensin converting enzyme inhibitor: drug interaction with salbutamol and bronchial response to histamine in normal subjects

Aims To investigate the effect of the angiotensin converting enzyme inhibitor, benazepril, on pulmonary function.
Methods We investigated the influence of benazepril, on lung function and the interaction with inhaled salbutamol (0.1 to 6.6  mg) and histamine (0.03 to 30.69  g  l⁻¹ ) in normal subjects. Benazepril 20  mg, salbutamol 8  mg, propranolol 160  mg, and placebo were given orally once daily over 10 days.
Results On day 8, there was no difference in the area under the salbutamol dose-response curves between benazepril, placebo and oral salbutamol ( P >0.05), propranolol shifted the curves to the right ( P <0.05). On day 10, histamine challenge resulted in following P D ₃₅sGaw values (geometric mean and 95% CI): with placebo 1.02 (0.95–1.09)  g  l⁻¹ , benazepril 1.04 (0.99–1.08), salbutamol 1.19 (1.13–1.25), propranolol 0.57 (0.50–0.65).
Conclusions Benazepril had no influence on baseline lung function, caused no interaction with inhaled salbutamol and the bronchial response to histamine was similar to placebo. However, our findings in normal subjects cannot be extrapolated automatically to asthmatics.     

Dose-response relationship and time-course of the effect of inhaled magnesium sulphate on airflow in normal and asthmatic subjects.

1. Magnesium is a dietary cation with a wide range of actions of potential relevance to asthma. 2. To determine the dose-response relationship and time-course of the effect of inhaled magnesium sulphate on the airway, we have studied the effect of 0, 90, 135, 180 and 360 mg of magnesium sulphate given by nebulizer on specific airways conductance (sGaw) in 20 normal subjects, and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), flow at 25% forced vital capacity (Vmax25) and peak expiratory flow (PEF) in 19 asthmatic subjects. 3. On five occasions after baseline measurements of airway calibre, one of the five doses of magnesium sulphate in 3 ml normal saline was administered by nebulizer in a randomized, double-blind design. Measurements of sGaw or FEV1, FVC, Vmax25 and PEF were made at 5 and 10 min after nebulization and at 10 min intervals thereafter up to 90 min. 4. There was no significant difference in the mean area under the curve (AUC) for change from baseline in sGaw or maximum increase from baseline between doses in normal subjects. 5. In asthmatic subjects there was no significant difference in the mean AUC for change from baseline in FEV1, FVC or Vmax25 when compared between doses by analysis of variance. There was a difference in the mean AUC for change from baseline in PEF between doses (ANOVA P for all groups 0.052) but this can be explained by a detrimental effect of the maximum dose of magnesium sulphate. 6. It would appear that inhaled magnesium does not act as a bronchodilator in normal or asthmatic subjects.     

[13C]-pantoprazole breath test to predict CYP2C19 phenotype and efficacy of a proton pump inhibitor, lansoprazole

Background  ¹³CO₂ is produced on metabolism of ¹³C-labelled-pantoprazole ([¹³C]-pantoprazole) by CYP2C19.
Aim  To investigate whether the [¹³C]-pantoprazole breath test can predict CYP2C19 status and efficacy of proton pump inhibitors (PPIs) in Japanese.
Methods  We classified 110 healthy volunteers as rapid metabolizers (RM), intermediate metabolizers (IM) or poor metabolizers (PM) of CYP2C19 by genotyping. Breath samples were collected at 10-min intervals for 60 min after dosing with 100 mg [¹³C]-pantoprazole. Changes in the carbon isotope ratios (¹³CO₂/¹²CO₂) in carbon dioxide in breath samples were measured and expressed as a delta-over-baseline (DOB) ratio (‰). Of the 110 subjects, twenty-two randomly selected subjects underwent intragastric pH monitoring on day 7 of dosing with 30 mg of lansoprazole.
Results  The DOB values of RMs were the highest and those of PMs the lowest of the three groups. Statistically significant differences were observed in the area-under-the-curve ( AUC )_20–60 min of DOB among the three groups. The mean 24-h intragastric pHs attained by lansoprazole 30 mg for 7 days were inversely correlated with the AUC _20–60 min of DOB.
Conclusions  [¹³C]-pantoprazole breath test can easily estimate the individual activity of CYP2C19 and predict the efficacy of a PPI (i.e. lansoprazole). This test would be useful for individualized medicine with a PPI.     

Picumeterol: dissociation of improvement in lung function and reduction of airways hyperresponsiveness in asthmatics

Aims The new potent and selective β₂-adrenoceptor agonist, GR 114297A (picumeterol) is the R-enantiomer of the racemic form, GR 63411B. Picumeterol has been shown to produce long-lasting relaxation of airways smooth muscle both in vitro and in vivo . We assessed the intrinsic activity of picumeterol by increasing intracellular levels of c-AMP and compared this with isoprenaline and salbutamol.
Methods In human atopic asthmatics, we have investigated the duration of action and efficacy of picumeterol and GR 63411B with regard to improvement in resting lung function (i.e. FEV₁ ) and airways responsiveness (i.e. P C ₂₀ ) to methacholine (MCh). The study design consists of two clinical parts each for one drug. Different asthmatics participated in the two studies, seven in the first part and eight in the second part. In human bronchial smooth muscle cells in vitro , we have investigated the intrinsic activity of picumeterol in increasing intracellular levels of cyclic AMP and compared it with isoprenaline and salbutamol.
Results In vivo , both drugs caused bronchodilatation with similar potency, but, their effects were short-lasting. Despite their bronchodilator activity, neither drug improved P C ₂₀, when compared with placebo. In vitro , picumeterol was found have intrinsic activity lower than the other β₂-adrenoceptor agonists tested.
Conclusions In the clinical studies, the bronchodilator potencies of picumeterol and GR 63411B were similar. However, both drugs were short-acting, which is at odds with their activity in vitro . Our data suggest that these compounds display dissociation between bronchodilator activity and protection against MCh-induced bronchoconstriction. These findings may be explained by low intrinsic activity and need further conformation.     

Histamine H2-receptor antagonists have no clinically significant effect on the steady-state pharmacokinetics of voriconazole

Aims  Voriconazole, a new triazole antifungal agent, is metabolized mainly by cytochrome P450s CYP2C19 and CYP2C9, and also by CYP3A4. The aim of this open-label, placebo-controlled, randomized, three-way crossover study was to determine the effects of cimetidine and ranitidine on the steady-state pharmacokinetics of voriconazole.
Methods  Twelve healthy male subjects received oral voriconazole 200 mg twice daily plus cimetidine 400 mg twice daily, voriconazole 200 mg twice daily plus ranitidine 150 mg twice daily, and voriconazole 200 mg twice daily plus placebo twice daily. Treatment periods were separated by at least 7 days.
Results  When cimetidine was administered with voriconazole, the maximum plasma voriconazole concentration ( C _max) and the area under the plasma concentration–time curve of voriconazole (AUC_τ) was increased by 18.3%[90% confidence interval (CI) 6.0, 32.0] and 22.5% (90% CI 13.3, 32.5), respectively. Concomitant ranitidine had no significant effect on voriconazole C _max or AUC_τ. Time of C _max ( t _max) elimination half-life ( t _1/2) or terminal phase rate constant ( k _el) for voriconazole were similar in all three treatment groups. Most adverse events were mild and transitory; two subjects were withdrawn due to adverse events.
Conclusions  Coadministration of the histamine H₂-receptor antagonists cimetidine or ranitidine does not affect the steady-state pharmacokinetics of voriconazole in a clinically relevant manner.     

Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man

Aims The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using N ^G-monomethyl-l-arginine (l-NMMA) on systemic and pulmonary haemodynamics.
Methods Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double-blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l-NMMA (4  mg  kg⁻¹  h⁻¹ ) with a front loaded bolus (4  mg  kg⁻¹ ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion ( t ₀ ) and after 4, 8, and 12  min ( t ₁, t ₂ and t ₃ ).
Results Infusion of l-NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t ₁ and persisted during the entire infusion period.
Conclusions These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.     

Stereoselective interaction between piroxicam and acenocoumarol

1 An open-label study was performed to assess the effect of piroxicam on the pharmacokinetics of acenocoumarol enantiomers.
2 Eight healthy male volunteers received an oral dose of 4  mg rac -acenocoumarol on days 1 and 8, plus 40  mg piroxicam orally 2  h before the anticoagulant on day 8. R- and S-acenocoumarol, piroxicam and their metabolites were measured in plasma over a 24  h interval.
3 The pharmacokinetics of R-acenocoumarol were markedly modified by piroxicam: C _max+28.0% (s.d.23.8), P <0.05; AUC(0,  24  h)+47.2% (21.5), P <0.005; and t _1/2+38.0% (34.5), P <0.01. A concomitant decrease of CL/ F was observed: −30.8% (10.0), P <0.0001. A similar, but statistically non-significant trend, was observed on the S-enantiomer: C _max: +9.5% (s.d.36.6), AUC(0,  24  h): +15.4% (23.4), t _1/2: +19.9% (42.0), and CL/ F: −9.8% (20.5). V/F remained unchanged for both enantiomers.
4 Piroxicam plasma AUC(0,  24  h) correlated closely with R- and Sacenocoumarol AUCs on day 1 ( r =0.901, P <0.005 and r =0.797, P <0.05, respectively), as well as with the difference of AUC between days 1 and 8 for R-acenocoumarol ( r =0.903, P <0.001) and S-acenocoumarol ( r =0.711, P <0.05).
5 Piroxicam markedly reduced acenocoumarol enantiomer clearance, with a greater effect on the more active R-isomer. This interaction, which occurs in addition to the well documented pharmacodynamic one (effect on platelets), is expected to result in increased anticoagulant effect.     

Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis

Aims Neoral is a new microemulsion form of cyclosporin. Pharmacokinetic reports in children are scarce. Therefore, we performed a pharmacokinetic study between Cyclosporin A (CsA) capsules and Neoral in paediatric patients with lupus nephritis.
Methods A single 5  mg  kg⁻¹ dose orally of either CsA capsules or Neoral was given to 10 paediatric patients (serum creatinine<1.5  mg dl⁻¹ ). CsA whole blood levels were measured for 24  h post-dose by h.p.l.c.
Results Neoral had a higher C _max and AUC( C _max: 943±176  ng  ml⁻¹; AUC: 4612±785  ng  ml⁻¹  h) than those of the CsA capsules ( C _max: 697±187  ng  ml⁻¹; AUC: 3483±873  ng  ml⁻¹  h; P <0.05). There was no difference in t _max and t _1/2,z between the two groups.
Conclusions CsA Neoral had improved absorption and bioavailability, which is similar to what is reported in adults. However, interpatient variability still existed. Careful drug monitoring and dose adjustment should be performed during treatment to avoid nephrotoxicity, especially in lupus nephritis.     

Effect of Sodium Hypochlorite on Specific Airway Resistance and Airway Reactivity in Guinea Pigs

Abstract

To evaluate the effect of sodium hypochlorite (NaOCl) on specific airway resistance (SRaw) and the possibility that NaOCl is involved in causing airway hyperreactivity, we studied the effect of exposure to NaOCl aerosol on SRaw and airway reactivity to inhaled histamine aerosol in intact, unanesthetized, spontaneously breathing guinea pigs. A 1-min inhalation of 1.2–10.0% NaOCl caused an increase in SRaw in three of six animals in a concentration-dependent manner. To assess the airway reactivity, the effective concentration of histamine that produced a doubling of baseline SRaw (EC₂₀₀His) was determined. A 5-min inhalation of 3.6% NaOCl aerosol caused an acute decrease in EC₂₀₀His without a corresponding change in SRaw, whereas a 5-min inhalation of normal saline caused no significant changes in SRaw and EC₂₀₀His. Therefore, a 5-min inhalation of 3.6% NaOCl induced airway hyperreactivity. On the contrary, a 15-min inhalation of 3.6% NaOCl did not cause significant changes in mean EC₂₀₀His values at 5 min, 5 hr, and 1 week after exposure. The mean SRaw at 5 hr after a 15-min inhalation of 3.6% NaOCl was higher than that of the baseline value. A 15-min inhalation of normal saline aerosol caused an increase in EC₂₀₀His i.e., reduced airway reactivity, 5 min after exposure. The increased EC₂₀₀His returned to baseline level at 5 hr and 1 week after exposure. A 15-min inhalation of normal saline caused no significant change in SRaw during the study period.

Our study indicates that acute NaOCl aerosol inhalation causes a temporary increase in SRaw and airway hyperreactivity to inhaled histamine in guinea pigs.     

H2-receptor antagonists and antacids have an aggravating effect on Helicobacter pylori gastritis in duodenal ulcer patients

Background : Antacids, such as aluminium–magnesium hydroxide (AlMg(OH)₃), or H₂-receptor antagonists, such as ranitidine, are common drugs used for treating peptic ulcer disease and acid-related symptoms.
Methods : In a prospective double-blind controlled study, 174 patients were randomized to a 4-week course of treatment with either AlMg(OH)₃ (acid-binding capacity: 280 mval/day) or ranitidine 300 mg for active Helicobacter pylori -associated duodenal ulcers (as determined by histology and the urease test). Before and after treatment, two biopsy specimens each were obtained from the antrum and corpus, and the grade and activity of gastritis, as well as H. pylori density, were determined using a score ranging from 0 = none to 4 = severe.
Results : Pre- and post-treatment histology were available for 138 patients (AlMg(OH)₃: 67, ranitidine: 71). Treatment with AlMg(OH)₃ significantly increased the activity of corpus gastritis (Wilcoxon signed-rank: P  = 0.0014), while ranitidine treatment significantly increased both the grade and activity of corpus gastritis ( P  = 0.0002 and P  = 0.0001 respectively). In the antrum, both regimens provoked a significant increase in the frequency of intestinal metaplasia, but this may be a consequence of sampling error.
Conclusions : Ranitidine and AlMg(OH)₃ have an aggravating effect on H. pylori gastritis in duodenal ulcer patients. This should be considered a side-effect of the respective drugs and is more pronounced with ranitidine.     

The interaction between propranolol and the novel antimigraine agent zolmitriptan (311C90)

Aims Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT_1B/1D agonist is under development as an acute oral treatment for migraine. Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investigated the effects of propranolol on the pharmacokinetics of, and cardiovascular responses to, zolmitriptan.
Methods A double-blind, randomized, crossover study of the effects of pre-treatment with propranolol 160  mg daily for 7 days or placebo on the pharmacokinetics and effects on blood pressure of a single 10  mg dose of zolmitriptan in 12 healthy volunteers.
Results Propranolol increased mean zolmitriptan C _max and AUC by 56% and 37% respectively; mean t _1/2 was prolonged from 3.1 to 4.0  h. Mean C _max and AUC of the pharmacologically active N -desmethyl metabolite were reduced by 24% and 11% respectively and the metabolite:parent AUC ratio (AUC_m/AUC_p ) fell from 0.46 to 0.26. Mean C _max and AUC for the inactive indole acetic acid metabolite were both reduced by 13% and AUC_m/AUC_p from 1.04 to 0.59. A small pressor effect of short duration was observed following zolmitriptan with mean peak rises of 13 and 11  mmHg in systolic and diastolic pressures respectively; propranolol had no effect on the pressor response.
Conclusions The results suggest that propranolol inhibits biotransformation of zolmitriptan but with no change in the small pressor response to zolmitriptan. It is therefore unlikely that the pharmacokinetic changes will lead to clinically important changes in pharmacological effects and dosage adjustment of zolmitriptan is not required in patients taking propranolol for migraine prophylaxis.     

Effect of age and gender on the pharmacokinetics of eprosartan

Aims To compare the pharmacokinetics of eprosartan between young (18–45 years) and elderly (65 years) men and between young men and young, premenopausal women (18–45 years).
Methods Twenty-four subjects (eight subjects/group) received a single 200  mg eprosartan oral dose followed by serial blood sampling over 24  h.
Results Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (≈98%) for the three groups. On average, AUC (0,∞) and C _max values were ≈2-fold higher in elderly men than young men [AUC (0,∞) 95% CI: 1.22, 4.34; C _max 95% CI: 0.98, 4.00]. Similarly, unbound AUC (0,∞) and C _max values were, on average, ≈2-fold higher in elderly men than young men [unbound AUC (0,∞) 95% CI: 1.29, 4.44; unbound C _max 95% CI: 1.02, 4.12]. t _max was delayed in the elderly men compared with young men, with a median difference of 2.5  h (95% CI: 1.00, 3.01  h).
Conclusions No gender differences were observed in the pharmacokinetics of eprosartan. There were ≈  two fold higher AUC and C _max values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200  mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.     

Attenuation by ACE inhibitor drugs of α-adrenoceptor sensitivity in human vessels: possible differences related to drug lipophilicity

Aims We investigated the effect of angiotensin converting enzyme inhibitors (ACEIs) on postsynaptic adrenoceptor sensitivity and compared the effect of the lipophilic ACEI, quinapril, and that of hydrophilic agent, enalapril in human vessels.
Methods α-adrenoceptor sensitivity was evaluated using the dorsal hand vein compliance technique. The dose–response curves of vasoconstriction to phenylephrine and prostaglandin F_2α were obtained in healthy male volunteers.
Results The ACEIs shifted the dose–response curve of phenylephrine to the right and raised the median effective dose (E D ₅₀; 189.3 (57.6  ng  min⁻¹ ) of phenylephrine. Following quinapril administration, E D ₅₀ increased to 481.1 (101.8  ng  min⁻¹ compared with 266.8 (55.8  ng  min⁻¹ after enalapril (95% CI for differences; 31.1–397.5  ng  min⁻¹ ). Quinapril administration had no effect on the dose–response curve of PGF_2α .
Conclusions ACE inhibition attenuates α-adrenoceptor sensitivity in human vessels. The effect of quinapril, a lipophilic ACEI, was greater than that of enalapril, a hydrophilic ACEI. Lipophilic ACEIs may be more potent in vasodilating effect than hydrophilic ACEIs. Angiotensin II concentration in tissue rather than that in plasma may contribute to the α-adrenoceptor sensitivity of the vessels.     

Enhancement of airway reactivity to histamine by isoprenaline and related beta-adrenoceptor agonists in the guinea-pig.

1. The effect of isoprenaline, adrenaline and salbutamol on airway reactivity to histamine was observed in anaesthetized, ventilated guinea-pigs. Airway reactivity was determined before and 20 min and 90 min after a 30-min i.v. infusion of each agonist by constructing cumulative dose-response curves from breath-by-breath measurements of the effect of different rates of i.v. infusion of histamine on lung resistance (RL) and dynamic compliance (Cdyn). 2. (+/-)-Isoprenaline infused i.v. for 30 min at a rate of 0.4 mumol h-1 kg-1 caused bronchodilatation and a fall in blood pressure. Recovery to starting values of RL and Cdyn occurred within 20 min of stopping the infusion. 3. Reactivity to histamine was greatly enhanced when measured 20 min and 90 min after stopping the infusion of (+/- )-isoprenaline. This was not an effect of the prior infusion of histamine or of the dissolving solution. 4. Infusion of (-)-isoprenaline for 30 min at a rate of 0.2 mumol h-1 kg-1 also enhanced reactivity to histamine. However, enhancement of reactivity to histamine was not demonstrable after infusion of (+)-isoprenaline at equal or higher dose rates. 5. Infusions of bronchodilator concentrations of adrenaline and salbutamol also enhanced airway reactivity to histamine, but the bronchodilator effect of salbutamol lasted longer than that of isoprenaline or adrenaline and the development of hyperreactivity was delayed. 6. After acute bilateral vagotomy, infusion of (+/- )-isoprenaline enhanced airway reactivity but only at the highest dose of histamine. 7. (+/-)-Isoprenaline did not enhance contractile responses to histamine in isolated preparations of first branch bronchi.(ABSTRACT TRUNCATED AT 250 WORDS)     

Validation of laser Doppler flowmetry coupled with intra-dermal injection for investigating effects of vasoactive agents on the skin microcirculation in man

OBJECTIVE: To determine the reproducibility of laser Doppler flowmetry coupled with intra-dermal saline delivery. METHODS: Delivery of saline was judged visually by two operators ( n=100), using a graduated syringe (Becton-Dickinson), by expelling saline onto a weighing boat. Volume was assessed by weight. Skin blood flow following intra-dermal injection of saline was assessed in 18 healthy volunteers; 10 attended twice to assess between-day reproducibility, and 8 attended once to assess between-site reproducibility. Results are expressed as mean value+/-SEM and 95% confidence interval for mean differences. RESULTS: There was no difference between operators in mean injection weight, both weights being 10.3+/-0.1 mg (mean difference 0.08, 95% confidence interval, CI -0.23 to 0.39 mg; n=100, P=0.9). Intra-dermal saline caused a nine-fold increase in blood flow (0.03+/-0.003 to 0.27+/-0.02 perfusion units, PU; n=18, P<0.001). This response had a rapid onset, with the maximal effect seen at 4 min and a duration of greater than 30 min. There was no difference in the magnitude of the response between the dominant and non-dominant arms, AUC was 2.9+/-0.4 and 2.9+/-0.4, respectively (mean difference -0.05, 95% CI -0.8 to 0.73 PU; n=18, P=0.93). However, there was a trend towards differences between study visits 1 and 2: AUC was 3.2+/-0.6 and 2.0+/-0.5, respectively (mean difference 1.2, 95% CI -0.03 to 2.43 PU; n=10, P=0.7). There was no difference in the magnitude of responses between different sites on the forearm ( n=64, P=0.6). CONCLUSIONS: These studies demonstrate that the technique of laser Doppler flowmetry coupled with intra-dermal injection is a safe, well-tolerated technique with good reproducibility. A trend towards reduced between-day reproducibility emphasizes the importance of vehicle control sites when investigating the effects of vasoactive compounds. This technique provides a reliable method for the intra-dermal delivery of drugs, despite the direct effect of injection of saline on blood flow.     

Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis C

Background  The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated.
Aim  To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin.
Patients and methods  Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment.
Results  At week 4, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.376, P  = 0.002) and AUC _0→12h of ribavirin plasma level ( r  = −0.277, P  = 0.018). At week 12, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.384, P  < 0.0001) and AUC _0→12h of ribavirin plasma level ( r  = −0.257, P  = 0.002). In genotype 1 patients, AUC _0→12h ribavirin and C _min were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12.
Conclusion  C_min of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.     

Diazepam–omeprazole inhibition interaction: an in vitro investigation using human liver microsomes

1 The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam (NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V _max /K _m ratio of 0.50–7.26  μl  min⁻¹  mg ⁻¹ protein.
2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K _i of 201±89  μm was obtained for the 3HDZ pathway ( K _m /K _i ratio of 3.0±0.9).
3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K_is of 121±45 and 188±73  μm respectively ( K _m /K _i ratios of 5.2±2.3 and 3.3±1.5 respectively).
4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.     

Effect of food and gender on the pharmacokinetics of tucaresol in healthy volunteers

Aims To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults.
Methods In a cross-over study, blood samples were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240  min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique.
Results The maximal plasma cobalamin concentration ( C _max ) after nasal administration of 750  μg hydroxocobalamin was 1900±900  pmol  l⁻¹ (mean±s.d.). The maximal plasma cobalamin concentration was reached in 35±13  min ( t _max ). The C _max after nasal administration of 1500  μg hydroxocobalamin was 3500±2500  pmol  l⁻¹ with a t _max of 28±16  min. Both the AUC(0,240  min) and AUC(0,00) increased significantly with an increase of the dose from 750  μg to 1500  μg ( P =0.037 and P =0.028, respectively). The nasal spray was well tolerated. No signs of irritation or local sensitivity were noted.
Conclusions The nasal absorption of hydroxocobalamin in healthy elderly adults is rapid, high and well tolerated.