Add-on therapy with doxazosin in patients with hypertension influences arterial stiffness and albuterol-mediated arterial vasodilation

What is already known about this subject

• Hypertension is associated with increased arterial stiffness and impaired endothelial function.
• Arterial vasodilation depends on endothelial function and can be regulated by β₂-adrenergic stimulation.
• Doxazosin is a known and potent antihypertensive agent. However, its effects on arterial stiffness and vasodilation have not been fully established.

What this study adds

Sixteen-week add-on antihypertensive therapy with 4 mg of doxazosin extended release daily:

• Reduces arterial stiffness.
• Improves albuterol-mediated, i.e. endothelium-dependent, arterial vasodilation.
• Does not influence nitroglycerin-mediated, i.e. endothelium-independent, arterial vasodilation.

Aims

Doxazosin is an antihypertensive agent with largely unknown effects on arterial stiffness and vasodilation. The aim of this study was to determine the effect of the addition of doxazosin extended-release (ER) to the standard management of hypertension in patients with inadequately controlled blood pressure (BP) on arterial stiffness and arterial vasodilation.

Methods

Twenty patients with inadequately controlled hypertension were treated with 4 mg doxazosin ER daily for 16 weeks as an adjunct to their existing antihypertensive regimen.

Results

Doxazosin ER add-on therapy was associated with significantly reduced systolic (P < 0.0001) and diastolic (P = 0.0003) BP, improved arterial stiffness (determined by digital volume pulse analysis (P = 0.048) and albuterol-mediated arterial vasodilation (P = 0.030).

Conclusions

Add-on therapy with 4 mg of doxazosin ER daily reduces BP and arterial stiffness and improves arterial vasodilation in response to adrenergic stimulation.     

Adherence to statin or aspirin or both in patients with established cardiovascular disease: exploring healthy behaviour vs. drug effects and 10-year follow-up of outcome

Aims

To characterize adherence in patients with established cardiovascular disease taking statins and aspirin and to estimate the effects of adherence due to health behaviour, a lack of beneficial drug effect, or both on recurrence of cardiovascular disease or all-cause mortality over 10 years.

Methods

A population-based cohort study using a record-linkage database in Tayside, Scotland. Subjects with cardiovascular disease (n = 7657; 4185 aspirin-alone cohort, 671 statin-alone cohort and 2801 combination use cohort) were studied between 1993 and 2003. The effects of adherence on recurrence of cardiovascular disease or mortality were assessed using Poisson regression model.

Results

In subjects taking both aspirin and statins, those adherent to statins but not aspirin had a lower risk of recurrence [adjusted risk ratio (RR) 0.64; 95% confidence interval 0.49, 0.82], but those adherent to aspirin but not statins has no such effect (adjusted RR 0.91; 0.72, 1.15), suggesting that adherence behaviour alone was not responsible for the beneficial effect. Within the group adherent to aspirin, ≥80% adherence to statins was associated with reduced recurrence compared with those poorly adherent (adjusted RR 0.76; 0.62, 0.94), but no such effect of aspirin was seen in those adherent to statins. Similar results were found for all-cause mortality.

Conclusions

Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients. Adverse outcome is more likely to be driven by foregone drug benefits.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Aspirin and statins are widely-used drugs in patients with cardiovascular disease.
• There is less information on healthy behaviour vs. drug effects.

WHAT THIS STUDY ADDS

• Long-term adherence to aspirin and statin treatments in patients with established cardiovascular disease has been investigated.
• Poor health behaviour is not a sufficient explanation of adverse outcome in poorly adherent patients.

     

The effect of age, gender, and body mass index on the pharmacokinetics and pharmacodynamics of vildagliptin in healthy volunteers

Aims

To evaluate the effect of age, gender, and body mass index (BMI) on the pharmacokinetics and pharmacodynamics of vildagliptin.

Methods

Forty healthy subjects received a single oral dose of 100 mg vildagliptin to assess the effects of age, gender, and BMI on the pharmacokinetics and pharmacodynamics, reflected by the time course of inhibition of DPP-4 activity, of vildagliptin.

Results

Peak concentration and exposure (AUC_(0–∞)) of vildagliptin were 17% (90% CI 2, 35%) and 31% (90% CI 18, 45%) higher in elderly vs. young subjects. Renal clearance was reduced by 32% (90% CI 17, 45%) in elderly subjects. The pharmacokinetics of vildagliptin were not significantly influenced by gender or BMI. Inhibition of DPP-4 activity was similar regardless of age, gender, or BMI.

Conclusions

The pharmacokinetics of a single oral 100 mg dose of vildagliptin were not affected by gender and BMI. Exposure to vildagliptin was higher in elderly patients, but this was not associated with any difference in the effect of DPP-4 inhibition. Based on these results, no vildagliptin dose adjustment is necessary for age, gender, or BMI.

What is already known about this subject

• Vildagliptin is a new, potent, and selective inhibitor of DPP-4.
• The efficacy and safety of vildagliptin in type 2 diabetes has been intensively studied in diverse subject populations.
• There has been little information published about the pharmacokinetics and pharmacodynamics of vildagliptin.

What this study adds

• No clinically relevant changes in pharmacokinetics or pharmacodynamics were observed between young and elderly, male and female, or high body mass index (BMI) and low BMI subjects.
• The results suggest that no dose modification is necessary for vildagliptin based on the age, gender, or BMI of a subject.

     

Gap in publication of comparative information on new medicines

AIMS

To determine the time-lag between the EU authorization of new medicines and the publications of the main randomized active control trials (RaCTs) used in the authorization process and to compare unpublished with published RaCTs of the same medicine.

METHODS

All RaCTs for new medicines with a new active substance, authorized between 1999 and 2003, were extracted from the European Public Assessment Reports (EPAR). Information about the publication status of RaCTs was obtained from the MEDLINE and EMBASE databases.

RESULTS

We identified 116 RaCTs for 42 new medicines; 28% of the RaCTs had been published at the moment of market authorization, 59% after 1 year, 78% after 2 and 83% after 3 years. Most of the rest of the studies remained unpublished after 3 years of follow-up. Unpublished RaCTs differed from published trials of the same medicine especially regarding therapeutic use and/or comparator. In some cases unpublished trials have influenced the risk : benefit asssessment of the registration authorities.

CONCLUSIONS

Most of the main RaCTs, relevant for assessing the added value of a new medicine, are published subsequent to market entry; some of these trials remain unpublished. We argue for a standardized public registration of the results of the main premarketing clinical trials as a condition for market authorization.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Randomized active control trials are used by health care professionals and reimbursement authorities for the assessment of the added value of a new medicine.
• Failing to publish the results of clinical trials limits making an evidence based assessment and conducting systematic reviews.

WHAT THIS STUDY ADDS

• About one-third of the comparative trials used in the authorization process are published at the moment of market authorization and about four out of five within 2 or 3 years. Most of the rest remain unpublished.
• Unpublished trials contain information regarding a different therapeutic use or a different comparator of the same medicine and, in some cases, have influenced the risk : benefit assessment of the registration authorities.
• A standardized public registration of results of the main premarketing trials is advocated to fill the publication gap.

     

Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate

Aims

To characterize the population pharmacokinetics of gemcitabine and its metabolite (dFdU) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design.

Methods

Gemcitabine and dFdU plasma concentration–time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates.

Results

Gemcitabine and dFdU pharmacokinetics were described by a two-compartment model with first-order elimination. The population mean (and between-subject variability, CV%) for clearance and volume of distribution of the central compartment (V_C) for gemcitabine were 2.7 l min⁻¹ (31%) and 15 l (39%), respectively, and 0.04 l min⁻¹ (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co-administration significantly decreased dFdU V_C by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone.

Conclusions

Co-administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.

What is already known about this subject

• Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin.
• The impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood.

What this study adds

• This study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions.
• Gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co-administration with oxaliplatin and were dependent on the order of administration.
• The clinical implications of this observation remain to be established.

     

Ezetimibe's effect on platelet aggregation and LDL tendency to peroxidation in hypercholesterolaemia as monotherapy or in addition to simvastatin

AIMS

To investigate the effect of lowering low-density lipoprotein-cholesterol (LDL-C) on platelet aggregation and LDL tendency to peroxidation by ezetimibe alone or with simvastatin in hypercholesterolaemia.

METHODS

Sixteen patients with LDL-C >3.4 mmol l⁻¹ received ezetimibe for 3 months (Part I). Twenty-two patients on fixed simvastatin dose with LDL-C >2.6 mmol l⁻¹ were enrolled (Part II). Part II patients continued simvastatin treatment 20 mg day⁻¹ for 6 weeks, then received 20 mg day⁻¹ simvastatin combined with ezetimibe 10 mg day⁻¹ for another 6 weeks. The tendency of LDL to peroxidation measured by lag time in minutes required for initiation of LDL oxidation and by LDL oxidation at maximal point (plateau) was measured before and after ezetimibe treatment.

RESULTS

Part I: Ezetimibe 10 mg daily for 3 months decreased plasma LDL-C level 16% (P = 0.002), prolonged lag time to LDL oxidation from 144 ± 18 min to 195 ± 16 min (P < 0.001), decreasing maximal aggregation from 83 ± 15% to 60 ± 36% (P = 0.04). Part II: Serum level LDL-C decreased 23% (P = 0.02) and lag time in minutes to LDL oxidation was prolonged from 55.9 ± 16.5 to 82.7 ± 11.6 (P < 0.0001) using combined simvastatin–ezetimibe therapy. There were no differences in platelet aggregation.

CONCLUSIONS

Ezetimibe was associated with decreased platelet aggregation and LDL tendency to peroxidation. Treatment with ezetimibe in addition to simvastatin has an additive antioxidative effect on LDL.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Statins demonstrate a pleiotropic effect which contributes beyond the hypocholesterolaemic effect to prevent atherosclerosis.

WHAT THIS STUDY ADDS

• Ezetimibe has an antioxidative effect when given as monotherapy or as an add-on to the statin, simvastatin.

     

Estimation of the impact of noncompliance on pharmacokinetics: an analysis of the influence of dosing regimens

AIMS

To determine whether, for oxybutynin and risperidone, drug exposure is better with less frequent dosing regimens than with regimens that require more frequent dosing.

METHODS

Pharmacokinetic models of oxybutynin (5 mg twice-daily and 10 mg once-daily) and risperidone (2 mg once-daily orally and 25 mg fortnightly intramuscular injection) were developed. Simulations of multiple doses were performed by use of stochastic models of dose-taking compliance and clinic visit attendance.

RESULTS

At therapeutic concentrations and with typical patterns of noncompliance, intramuscular injections of risperidone resulted in a 41% (SD 12%) greater pharmacokinetic coverage than the oral dose, 76% (SD 10%) vs. 35% (SD 7%). No discernable differences were evident between once- and twice-daily formulations of oxybutynin, 29.2% (SD 10%) vs. 29.0% (SD 13%).

CONCLUSIONS

For equivalent doses for each drug, the longer acting preparation of risperidone, but not oxybutynin, is pharmacokinetically more forgiving of noncompliance than the shorter acting counterparts. Further analysis is required to confirm whether these observations are valid clinically.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Patient compliance is better with formulations that require less frequent dosing than with formulations that require more frequent dosing.
• Intramuscular risperidone and long-acting oxybutynin are two examples of medicines reformulated for less frequent dosing.
• However, it is not clear whether better compliance with less frequent dosing regimens translates to improved therapeutic outcome.

WHAT THIS STUDY ADDS

• At equivalent daily doses and typical patterns of compliance, fortnightly intramuscular depot administrations of risperidone provide better pharmacokinetic coverage than once-daily oral dosing.
• Once-daily dosing of oxybutynin is no better at maintaining pharmacokinetic exposure than twice-daily dosing at half strength.
• The use of simulated compliance data as input to pharmacokinetic models is useful to assess the impact of noncompliance on internal drug exposure.

     

Clindamycin and taste disorders

What is already known about this subject.

• The antibiotic clindamycin has a bitter taste when it is used orally.

What this study adds

• A case series on oral as well as i.v. use of clindamycin associated with taste disorders is presented.
• After corrections in a case-by-case analysis for several possible confounders such as indication, clindamycin is disproportionally associated with taste disorders.
• Serum and hence saliva and sputum clindamycin levels seem to be responsible for this reversible adverse drug reaction.

Aims

Topical use of clindamycin has been associated with taste disorders in the literature, but little is known about the nature of this adverse drug reaction. The aim of this article was to describe reports of clindamycin-induced taste disorders and to analyse the factors involved.

Methods

The adverse drug reaction database of the Netherlands Pharmacovigilance Centre was searched for reports concerning taste disorders with antibiotics. Clinical review of the cases and statistical analysis with logistic regression were performed. Characteristics of patients who reported taste disorders were compared for age, gender and formulation in clindamycin vs. other antibiotic users.

Results

Taste disorders were reported in seven (18%) of the clindamycin cases. In five reports an oral formulation was involved, in one report intravenous (i.v.) administration and in one report both formulations were used. Latency was <1 day after start and in one case taste disorders were present repeatedly at 10 min after every i.v. application. The adjusted reporting odds ratio was 7.0 (95% confidence interval 2.8, 17.3) and supports a possible causal relationship.

Conclusions

The association of clindamycin and taste disorders is supported by disproportionality analysis and seems to be independent of possible confounders such as age, gender and infections. The case reports suggest a role for clindamycin concentrations excreted in body fluids like saliva.     

A signal of increased risk of hypoglycaemia with angiotensin receptor blockers caused by confounding

AIMS

To study reporting of hypoglycaemia in angiotensin receptor blocker (ARB) users, and to investigate the possibility of confounding.

METHODS

The French pharmacovigilance database was examined for an association between hypoglycaemia and ARBs or other drugs using reports notified between 1996 and 2005. This association was also tested in patients taking or not taking antidiabetic agents (ADAs) using reporting odds ratios (ROR).

RESULTS

Hypoglycaemia was mentioned in 807 of the 174 595 reports entered during the study period. Overall hypoglycaemia was associated with the use of ARBs [ROR 2, 95% confidence interval (CI) 1, 3] and with the use of ADAs (ROR 32, 95% CI 27, 37). Moreover, the use of ARBs was associated with the use of ADAs (OR 7, 95% CI 6, 8). Considering separately reports with and without ADA, the association of ARB use with a higher risk of hypoglycaemia disappeared (OR 0.4, 95% CI 0.2, 0.8 and OR 2, 95% CI 1, 3, respectively).

CONCLUSION

A signal indicating an association between ARB use and hypoglycaemia was found in the French pharmacovigilance database. This signal disappeared after stratification on ADA use, thus suggesting confounding by indication. Moreover, the association between ARB use and hypoglycaemia was negative in ADA users.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Spontaneous reporting is a valuable way to provide early detection for safety signals related to drug use.
• Due to the increasing size of pharmacovigilance databases, data-mining and other automated methods for signal generation are more and more often used.
• Even if these methods are very useful, they do not allow, for every particular association, an automated exploration of the multiple sources of confounding.

WHAT THIS STUDY ADDS

• An association between angiotensin receptor blockers use and hypoglycaemia was found in the French pharmacovigilance database.
• This signal disappeared after stratification on antidiabetic drug use, suggesting confounding by indication.
• The association between hypoglycaemia and angiotensin receptor blocker use was actually less than expected in concomitant antidiabetic drug users.

     

The human paraoxonase-1 phenotype modifies the effect of statins on paraoxonase activity and lipid parameters

Aims

Human serum paraoxonase-1 (PON1) protects lipoproteins against oxidation by hydrolysing lipid peroxides in oxidized low-density lipoprotein, therefore it may protect against atherosclerosis. One of the two common PON1 gene polymorphisms within the PON1 gene is the Q192R, whose prevalence can be estimated by phenotype distribution analysis. The goal of this study was to clarify the role of PON1 phenotypes on the effect of three different statins on paraoxonase activity and lipid parameters.

Methods

One hundred and sixty-four patients with type IIb hypercholesterolaemia were involved in the study. We examined the effect of 10 mg day⁻¹ atorvastatin, 10/20 mg day⁻¹ simvastatin and 80 mg day⁻¹ extended-release fluvastatin treatment on lipid levels and paraoxonase activity in patients with different PON1 phenotypes. The phenotype distribution of PON1 was determined by the dual substrate method.

Results

Three months of statin treatment significantly increased paraoxonase activity in every statin-treated group. In patients with AB+BB phenotype, statin treatment was significantly more effective on paraoxonase activity than in the AA group. Statin treatment more effectively decreased triglyceride levels in the AB+BB group compared with the AA group in the whole study population and in the simvastatin-treated group. Atorvastatin treatment was significantly more effective on apolipoprotein B levels in patients with AB+BB phenotype than in the AA phenotype group.

Conclusions

The PON1 phenotype may be a novel predictive factor for the effectiveness of statin treatment on PON1 activity and serum lipid levels; however, different types of statins may exert different effects on these parameters.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• It has been suggested that the human paraoxonase-1 (PON1) genotype is an important determinant of the therapeutic response given to statin treatment.
• It is also known that the PON1 activity status is a better predictor of coronary heart disease risk than any of the known PON1 genotypes.
• Our goal was to answer this previously uninvestigated, still clinically relevant question: does the PON1 phenotype have an impact on the paraoxonase-activating and lipid-lowering effect of different types of statins.

WHAT THIS STUDY ADDS

• All the statins (atorvastatin, simvastatin and fluvastatin) included in this study were able to increase serum paraoxonase activity and decrease triglyceride levels effectively; however, this response seemed to be more significant in patients with AB+BB PON1 phenotype than in those bearing AA PON1 phenotype.
• Furthermore, the apolipoprotein B-lowering effect of atorvastatin was also found to be PON1 phenotype-dependent.
• Our results indicate that the PON1 phenotype may be a novel predictive factor for the effectiveness of statin treatment on PON1 activity and serum lipid levels; however, different types of statins may exert different effects on these parameters.

     

The concentration of oxazepam and oxazepam glucuronide in oral fluid, blood and serum after controlled administration of 15 and 30 mg oxazepam

AIMS

To measure and compare the concentration–time profiles of oxazepam and oxazepam glucuronide in blood, serum and oral fluid within the scope of roadside testing.

METHODS

Biological samples were collected from eight male subjects after ingestion of 15 or 30 mg oxazepam on separate dosing occasions with an interval of 7 days. The concentration–time profiles of oxazepam and oxazepam glucuronide were fitted by using a one-compartment model.

RESULTS

For oxazepam and oxazepam glucuronide, the mean oral fluid/blood ratios were 0.05 (range 0.04–0.07) and 0.004 (range 0.002–0.006), respectively. The concentration–time profiles in oral fluid paralleled those in blood.

CONCLUSION

After oral administration of therapeutic doses of oxazepam, concentrations in oral fluid are very much lower than those in blood, and those of oxazepam glucuronide are much lower than those of the parent compound. Nevertheless, assay of oral fluid for oxazepam can be used to detect recent ingestion of the drug in drivers suspected of impaired driving performance.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Concentration–time profiles of drugs in oral fluid generally run parallel to those in blood.
• In general, oral fluid contains more parent drug than metabolites.
• For some benzodiazepines it has been shown that concentrations are lower in oral fluid than in blood.

WHAT THIS STUDY ADDS

• The concentration–time profile of oxazepam in oral fluid after a single dose of oxazepam runs parallel to blood and is dose dependent.
• Concentration ratios (oral fluid/blood and oral fluid/serum) of oxazepam and oxazepam glucuronide after controlled intake of a single dose of oxazepam are presented.

     

Acute passive cigarette smoke exposure and inhaled human insulin (Exubera) pharmacokinetics

AIMS

Relative to nonsmokers, the bioavailability of inhaled human insulin (Exubera®; EXU) is markedly increased in chronic smokers. The pharmacokinetics of EXU following passive cigarette smoke exposure is unknown.

METHODS

In an open-label, crossover study, healthy nonsmoking volunteers received two treatments in randomized sequence separated by a 2-week wash-out: (i) EXU 3 mg with no passive smoke exposure and (ii) EXU 3 mg after passive smoke exposure (atmospheric nicotine levels 75–125 μg m⁻³) for 2 h. Blood samples were obtained at prespecified times up to 6 h after EXU administration.

RESULTS

Twenty-seven subjects completed both study periods. Mean plasma insulin AUC₀₋₃₆₀ decreased by 17% [ratio 83%, 95% confidence interval (CI) 68.8, 99.5] and mean C_max by 29% (ratio 71%, 95% CI 59.8, 83.1) after passive cigarette smoke exposure. The median (range) t_max was 60 min (20–120 min) and 75 min (20–360 min) in the EXU with no exposure and EXU passive exposure groups, respectively. EXU was well tolerated.

CONCLUSIONS

Unlike active chronic smoking, acute passive cigarette smoke exposure modestly decreases EXU bioavailability and thus should not increase hypoglycaemia risk. These results are consistent with those from published literature involving technetium-labelled diethylenetriamine penta-acetic acid and suggest that passive cigarette smoke exposure causes an acute decrease in lung permeability vs. active smoking, which causes an increase in permeability.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Active cigarette smoking is associated with increased permeability of the pulmonary alveolar epithelium, resulting in faster absorption of inhaled drugs such as Exubera® (EXU). Absorption of EXU is increased approximately twice to four times as much in chronic smokers compared with nonsmokers.
• The rate of clearance of radioaerosols such as technetium-labelled diethylenetriamine penta-acetic acid is decreased in response to passive smoke exposure.

WHAT THIS STUDY ADDS

• Passive smoke exposure causes a decrease in lung permeability, an effect opposite to that of active smoking.
• Acute passive smoke exposure results in a decrease in EXU bioavailability and does not create a risk of hypoglycaemia.
• These results are consistent with previous studies of radioaerosol lung clearance.