Proton pump inhibitor-induced acute interstitial nephritis

What is already known about this subject

• In several case reports the use of omeprazole has been associated with interstitial nephritis.
• Recently there have been reports linking other proton pump inhibitors (PPIs) with interstitial nephritis.

What this study adds

• We present supplementary cases received by the Netherlands Pharmacovigilance Centre Lareb, concerning interstitial nephritis in users of PPIs including omeprazole, pantoprazole and rabeprazole.
• In this case series seven patients are presented. In six cases they recovered spontaneously after cessation of the PPI, in one case the patient recovered after treatment with a corticosteroid.
• Further support for this association comes from the worldwide adverse drug reaction database of the World Health Organization.
• This report shows that interstitial nephritis can occur with all PPIs. Health professionals should be aware of this potential serious adverse drug reaction.

Aim

To investigate the association between the use of proton pump inhibitors (PPIs) and acute interstitial nephritis (AIN).

Methods

The Netherlands Pharmacovigilance Centre Lareb received seven case reports of AIN induced by various PPIs. In five of the reports it was mentioned that the diagnosis was confirmed by a renal biopsy.

Results

The time to onset varied between hours to 4 months. In all cases but one the patient spontaneously recovered after withdrawal of the offending agent. In one case the patient received treatment with prednisolone and recovered. In one patient a rechallenge was done 9 days after the initial event. Within 12 h of re-exposure the patient developed symptoms of AIN.

Conclusions

The mechanism of drug-induced AIN is unknown, but an immunological mechanism is suspected. Our reports show no relation between dosage, latency, time to recovery, age or gender, supporting the hypothesis that the aetiology of AIN is immunological. Lareb has received reports of AIN with the use of omeprazole, pantoprazole and rabeprazole. This shows that AIN is a complication associated with the whole group of PPIs and not only omeprazole. It is important for health professionals to be aware of this adverse drug reaction, because an accurate and timely diagnosis and withdrawal of the offending drug can prevent potentially life-threatening renal failure.     

Knowledge creation about ADRs – turning the perspective from the rear mirror to the projector?

Aims

Spontaneous reports of adverse drug reactions (ADRs) are often the only documentation used to justify the recall of drugs from the market. The purpose of this study was to investigate whether it would have been possible to foresee serious ADR cases based on available information on ADRs reported in Phase II and III clinical trials before marketing.

Methods

We conducted a retrospective analysis of reported ADR data in Phase II/III clinical trials in the registration material for three different ADR scenarios: (i) trovafloxacin/alatrofloxacin and hepatotoxicity; (ii) tolcapone and hepatotoxicity and neuroleptic malignant syndrome; and (iii) rituximab and cytokine release syndrome. We chose the scenarios because they were of serious character and caused great damage to the patients and because of different outcomes of the scientific discussions in the regulatory agencies.

Results

In all three cases, the registration material contained observations of ADRs, but there had been no follow-up on these observations. ADRs were mentioned in the summary of product information (SPC) purely as information, to some extent accompanied by recommendations. The information was not converted into new knowledge and remained tacit knowledge embedded in the SPCs disseminated to health professionals/prescribers.

Conclusions

The registration material analysed contained information about ADRs that were reported later, meaning that it would have been possible to foresee the occurrence of the ADRs at the time of licensing. More active utilization of the information from Phase II/III clinical trials is recommended to prevent the appearance of unexpected ADRs and further emphasis in SPC warnings to doctors about possible serious ADRs.

What is already known about this subject?

• Serious and unexpected adverse drug reactions (ADRs) have been reported shortly after marketing of a number of drugs.
• Review of ADR cases by the regulatory authorities has resulted in suspension of drugs or restrictions in product information.

What this study adds?

• Information about serious and unexpected ADRs of three drugs with reported serious ADRs was already present in the registration files.
• Observations of these ADRs were not investigated further before marketing.
• A more active utilization of the ADR information in premarketing studies could probably prevent the appearance of unexpected and serious ADR cases after marketing.

     

Absolute bioavailability of imidafenacin after oral administration to healthy subjects

Aims

To investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects.

Methods

Fourteen healthy male subjects, aged 21–45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry.

Results

The absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 ± 6.3 l h⁻¹. The steady-state volume of distribution was 122 ± 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 ± 1.08 l h⁻¹, demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUC_t of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study.

Conclusions

The absolute mean oral bioavailability of imidafenacin was determined to be 57.8%. Imidafenacin was well tolerated following both oral administration and i.v. infusion.

What is already known about this subject

• The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively.
• The pharmacokinetic profiles of imidafenacin after oral administration have been revealed.
• Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4.

What this study adds

• The absolute bioavailability of imidafenacin in human is 57.8%.
• The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed.
• The formation of metabolites in the plasma is caused mainly by first-pass effects.

     

Serotonin transporter polymorphism and bleeding time during SSRI therapy

AIMS

Selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, are associated with an increased risk of bleeding disorders, probably due to decreased platelet serotonin levels. Polymorphisms in the serotonin transporter gene (5-HTT) may influence the risk of SSRI-induced bleedings. The aim of this study was to investigate whether and to what extent the serotonin transporter polymorphism increases the bleeding time in paroxetine users.

METHODS

A prospective study, using routinely collected hospital and pharmacy data, was conducted among 43 patients between 18 and 70 years old and on >4 weeks of paroxetine therapy. The genotype for the serotonin transporter (5-HTTLPR), trough paroxetine levels, platelet function analyser (PFA)-closure time (collagen/epinephrine) and a complete blood count were assessed.

RESULTS

No significant difference was seen between the SS, SL, LL genotypes of the serotonin transporter and the PFA-closure time. None of the covariates had a significant influence on the association between the serotonin transporter polymorphism and the PFA-closure time. Age and von Willebrand factor showed the largest contribution, but not significant. No difference was seen between the PFA-closure time and the frequency of bruising and spontaneous bleedings between patients with at least one S allele and with the LL genotype.

CONCLUSION

Our prospective study does not support the assumption that paroxetine can cause a prolonged PFA-closure time during paroxetine therapy due to a serotonin transporter polymorphism. Old age, use of platelet inhibitors and a history of gastrointestinal bleeding remain the focus for SSRI-induced bleeding complications.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• From case reports it has become clear that selective serotonin reuptake inhibitors (SSRIs) can cause bleeding disorders.
• The causative mechanism is as yet unknown.
• Several publications have described the relationship between the serotonin transporter genotype and the prevalence of certain diseases such as depression, but few have focused on the relationship with side-effects of antidepressive drugs such as SSRIs.

WHAT THIS STUDY ADDS

• This study suggests that the association between SSRI therapy and prolonged bleeding time may not be related to the polymorphism of the serotonin transporter (5-HTTLPR) investigated.

     

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.

     

Efavirenz concentrations in HIV-infected patients with and without viral hepatitis

AIMS

Data on efavirenz in HIV/viral hepatitis co-infected patients is non-consensual, probably due to liver function heterogeneity in the patients included.

METHODS

A case control study was performed on 27 HIV-infected patients, with controlled and homogenous markers of hepatic function, either mono-infected or co-infected with HBV/HCV, to ascertain the influence of viral hepatitis on efavirenz concentrations over a 2-year follow-up period.

RESULTS

No differences were found in efavirenz concentrations between groups both during and at the end of the follow-up period: control (2.43 ± 1.91 mg l^–1) vs. co-infected individuals (2.37 ± 0.37 mg l^–1).

CONCLUSION

It was concluded that HBV/HCV infections in themselves do not predispose to an overexposure to efavirenz.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• HIV-1 co-infection with HBV/HCV is the most important factor determining efavirenz-induced liver toxicity. Higher efavirenz plasma concentrations have been reported in these patients facilitating concentration drug-related adverse effects.
• It is not known whether changes in efavirenz disposition are due to the hepatitis infection/inflammation or to liver failure. As a consequence, the guidelines for the application of therapeutic drug monitoring of efavirenz in HBV/HCV co-infected patients have not been established.

WHAT THIS STUDY ADDS

• The present study has shown that HBV/HCV infection in itself does not predispose to higher efavirenz plasma concentrations. In the absence of hepatic failure, the risk of efavirenz concentration-dependent toxicity is not increased.
• Thus, therapeutic drug monitoring indications in co-infected patients with hepatic function within the normal range should be the same as in HIV-1 mono-infected patients.

     

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.

     

Incidence of fatal adverse drug reactions: a population based study

Aims

To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

Methods

Every seventh randomly selected deceased in three counties in South-east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug-related fatalities.

Results

Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

Conclusions

The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.

What is already known about this subject

• Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.
• The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.
• In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

What this study adds

• Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.
• Haemorrhages amount to almost two-thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.
• Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

     

Exposure-response analysis reveals that clinically important toxicity difference can exist between bioequivalent carbamazepine tablets

AIMS

To assess whether, using the current regulatory criteria, therapeutically important differences can exist between bioequivalent carbamazepine (CBZ) tablets. A secondary goal was to demonstrate quantitatively the relationship between the risk of neurological adverse effects to orally ingested CBZ and the rate of absorption.

METHODS

Results of a bioequivalence study by Olling et al. (Biopharm Drug Dispos 1999; 20: 19–28) were reanalysed. Following an exploratory data analysis step, a mixed-effect pharmacokinetic–pharmacodynamic (PK–PD) model was built to describe the dependence of adverse events on the CBZ concentration.

RESULTS

Rapid development of tolerance was demonstrated for most neurological adverse effects, with a characteristic half-life of 02.29 h and an initial EC50 of 2.33 mg l⁻¹. The resulting tolerance PK–PD model was characterized further using the tools and terminology of sensitivity analysis. It was demonstrated that the maximum concentration (C_max) exhibits poor PK and PD sensitivities, and that clinically significant differences can exist between formulations which otherwise comply with the bioequivalence requirements. In contrast, another PK metric, the partial AUC, was a much better marker of the early neurological adverse events observable during the absorption phase of the drug.

CONCLUSIONS

In clinical and regulatory considerations, the development of acute tolerance for adverse effects of CBZ must be taken into account. Partial AUC reflects more sensitively the risk of adverse events than C_max. Instead of the current trend of tightening of the bioequivalence criteria for narrow therapeutic index drugs, the use of alternative, more sensitive PK metrics is proposed.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The occurrence of central nervous system-related adverse effects has been apparently related to the absorption rate of carbamazepine (CBZ).
• However, the differing absorption rate metrics of four carbamazepine formulations in a bioequivalence study were unclearly associated with the incidence of adverse effects.

WHAT THIS STUDY ADDS

• The relationship between the incidence of most neurological adverse effects and the absorption rate of CBZ was quantitatively established.
• A mixed-effect PK–PD model demonstrated the rapid development of acute tolerance to these effects.
• Characterization of PD and PK–PD sensitivities showed that clinically significant differences in toxicity can exist between bioequivalent CBZ formulations.

     

Adverse drug reaction monitoring in a secondary care hospital in South India

Aims

To ascertain the current burden of ADRs at a Government hospital in Ooty and to assess the severity of reported ADRs and the additional financial burden associated with ADRs.

Methods

A prospective, spontaneous reporting study was conducted over a period of 9 months of inpatient admissions to the medical wards, co-ordinated by clinical pharmacists. The WHO definition of an ADR was adopted. The Naranjo algorithm scale was used for causality assessment. Confirmed ADRs were classified according to the Wills & Brown [7] method and assessed for severity and patient outcomes. The average cost incurred in treating the ADRs was calculated.

Results

Of the total of 187 adverse drug events (ADEs) reported, 164 reports from 121 patients were confirmed as ADRs, giving an overall incidence of 9.8%. This included 58 (3.4%) ADR related admissions and 63 (3.7%) ADRs occurring during the hospital stay. About two thirds of the reactions (102, 62.2%) were classified as probable. The majority of the reactions (88, 53.7%) were mild. Most patients (119, 72.6%) recovered from the incidence. The majority of the reactions were of type H (100, 61%) which indicates that they were not predictable and not potentially preventable. An average cost of 481 rupees (£6) was spent on each patient to manage ADRs.

Conclusions

The incidence and severity of ADRs documented in our study are lower than those reported in comparable populations in Western studies but more than those reported in India.

What is already known about this subject

• The benefits of adverse drug reaction (ADR) monitoring are well-known.
• Poor awareness and nonavailability of a central co-ordinating body resulted in lack of ADR monitoring in India.
• The National Pharmacovigilance Programme was recently initiated, encouraging ADR monitoring in selected centres, including our centre.

What this study adds

• This is the first study of its kind at GHQH, Ootacamund that has provided insight into the burden of ADRs here.
• The incidence and severity of ADRs documented in our study is lower than those reported in comparable populations in Western studies but more than those reported in India.

     

Thrombolysis or nothing for acute myocardial infarction? It's all the same!

AIMS

To assess the reliability of equivalence trials we tested whether the no-thrombolysis approach was equivalent to thrombolysis with streptokinase (SK) in acute myocardial infarction.

METHODS

We applied the hypothesis of an equivalence trial of a recombinant plasminogen activator and SK to the GISSI-1 control group.

RESULTS

In at least one of three subsets randomly extracted from the GISSI database the equivalence criterion was satisfied, i.e. death rates in patients given SK or not were similar enough to consider the no-thrombolysis regimen equivalent to thrombolytic treatment. Two-thirds of 100 replications of the sampling gave this result.

CONCLUSIONS

These findings suggest the unreliability of equivalence trials, which should neither be adopted by the scientific community nor accepted by the regulatory authorities.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The methodological and ethical value of equivalence and non-inferiority trials is questioned.
• These studies are still increasingly used in drug evaluation and accepted by the scientific community and the regulatory authorities.

WHAT THIS STUDY ADDS

• By applying the hypothesis of an equivalence trial of saruplase and streptokinase (SK) we proved that the no-thrombolysis approach in the GISSI trial was equivalent to thrombolysis with SK, i.e. death rates in patients given SK or not were similar enough to consider the no-thrombolysis regimen equivalent to thrombolytic treatment.
• These data illustrate the unreliability of equivalence trials, which can even disprove consolidated clinical evidence such as the efficacy of thrombolysis in acute myocardial infarction.
• Equivalence trials should not be considered an option by the scientific community and should not be accepted as a basis for marketing authorization by the regulatory authorities.

     

Is there evidence for biased reporting of published adverse effects data in pharmaceutical industry-funded studies?

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Industry-funded studies tend to emphasize favourable beneficial effects of the sponsor''s product, but we do not know if reports of adverse effects are downplayed.
• Pharmaceutical companies are required to collate and accurately report adverse effects data in order to fulfil regulatory requirements.

WHAT THIS STUDY ADDS

• The bias found in the studies looking at the association between industry funding and reporting of beneficial effects may not be as prominent when considering adverse effects data.
• Industry-funded studies do not appear to differ from non-industry-funded studies in reporting the raw adverse effects data, but the interpretation and conclusions may be slanted to favour the sponsor''s product.
• Readers of industry-funded studies should critically examine the raw safety data themselves rather than be swayed by the authors’ interpretation.

AIM

To investigate whether adverse effects data for the sponsor''s product are presented more favourably in pharmaceutical industry-funded studies than in non-industry-funded studies.

METHODS

We conducted a systematic review of methodological evaluations that had assessed the relationship between industry funding and the reported risk of adverse effects. Searches were undertaken in 10 databases and supplemented with other sources of information such as handsearching, citation searching, checking conference proceedings and discussion with experts. Two reviewers independently screened the records and carried out data extraction for potentially relevant papers. We included studies that compared the results and interpretation of the adverse effects data according to funding source (e.g. adverse effects data in pharmaceutical industry research vs. data from nonprofit organizations, or from one manufacturer vs. another). Methodological evaluations were excluded if categories of funding source were not explicitly specified by the researchers, and if we were uncertain that industry-funded studies were present in the evaluation.

RESULTS

The search strategy yielded 4069 hits, of which six methodological evaluations met our inclusion criteria. One survey of 370 trials covering a wide range of topics found that trials with industry sponsors had more complete reporting of adverse effects compared with non-industry-funded trials, whereas another survey of 504 inhaled corticosteroid studies showed no apparent difference after confounding factors were adjusted for. In contrast, we found evidence from post hoc subgroup analyses involving two products where the likelihood of harm was of a lower magnitude in manufacturer-funded studies compared with nonmanufacturer-funded studies. There is also evidence from four methodological evaluations that authors with industry funding were more likely than authors without pharmaceutical funding to interpret and conclude that a drug was safe, even among studies that did find a statistically significant increase in adverse effects for the sponsored product.

CONCLUSIONS

Our review indicates that industry funding may not be a major threat to bias in the reporting of the raw adverse effects data. However, we are concerned about potential bias in the interpretation and conclusions of industry-funded authors and studies.     

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.     

Effect of acute paracetamol overdose on changes in serum and urine electrolytes

What is already known about this subject

• Paracetamol causes renal failure in overdose. Experimental studies have shown that paracetamol can inhibit COX II systemically in a manner similar to selective COX-II inhibitors.
• In overdose nonsteroidal anti-inflammatory drugs such as ibuprofen, cause dose-dependent increase in urinary potassium excretion (FeK) and sodium retention, probably due to vasoconstriction.

What this study adds

• Paracetamol overdose is associated with dose-related hypokalaemia and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose.
• This effect seems likely to be via cyclo-oxygenase inhibition and may be separate from the nephrotoxic effects of paracetamol.

Aims

To investigate the effects of acute paracetamol overdose on renal function, serum and urine electrolyte excretion in man.

Methods

Two studies were performed in patients admitted with paracetamol overdose: a retrospective study examining changes in serum electrolytes, and a prospective study evaluating changes in serum and urine electrolytes. A control group with SSRI overdose was included in the prospective study.

Results

There was a significant dose-dependent relationship between admission (4 h) paracetamol concentration and fall in serum potassium in the retrospective study (P < 0.01) and a significant positive relationship between serum paracetamol at 4 h and fractional excretion of potassium at 12 h postingestion (P < 0.01) in the prospective study. No changes were seen in the control group. No cases developed renal failure.

Conclusions

Paracetamol overdose is associated with dose-related hypokalaemia, and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose perhaps via cyclo-oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol.     

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.

     

Enriched enrollment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Enriched enrolment (the exclusion of non-responders or specific inclusion of responders) is believed to add both to trial sensitivity and to the measured effect of an intervention.
• Enriched enrolment lacks specific definition, and the extent of any differences between results with non-enriched recruitment and enriched enrolment is not known.
• Enriched enrolment is thought to have influenced neuropathic pain trials.

WHAT THIS STUDY ADDS

• The paper suggests definitions for complete and partial enriched enrolment, and applies those definitions to trials of pregabalin and gabapentin in neuropathic pain.
• The effect of enrichment was small, and especially in pregabalin trials with the best data, no difference was found between partial enrichment and no enrichment.
• The effects of complete enrichment are unknown.

AIMS

Enriched enrolment study designs have been suggested to be useful for proof of concept when only a proportion of the diseased population responds to a treatment intervention. We aim to investigate whether this really is the case in trials of pregabalin and gabapentin in neuropathic pain.

METHODS

We defined ‘complete’, ‘partial’ and ‘non-enriched’ enrolment, and examined pregabalin and gabapentin trials for the extent of enrichment and for effects of enrichment on efficacy and adverse event outcomes.

RESULTS

There were no studies using complete enriched enrolment; seven trials used partial enriched enrolment and 14 non-enriched enrolment. In pregabalin trials the maximum extent of enrichment was estimated at about 12%. Partial enriched enrolment did not change estimates of efficacy or harm. Over 150–600 mg maximum daily dose there was strong dose dependence for pregabalin.

CONCLUSIONS

A benefit of partial over non-enriched enrolment could not be demonstrated because the degree of enrichment was rather small, and possibly because enrichment produced little enhancement of treatment effect. Whether a greater degree of enrichment would result in important differences is unknown. Researchers reporting clinical trials with any enrichment must describe both process and extent of enrichment. As things stand, the effects of enriched enrolment remain unknown for neuropathic pain trials.     

Sitagliptin, an dipeptidyl peptidase-4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects

AIMS

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an incretin enhancer that is approved for the treatment of Type 2 diabetes. Sitagliptin is mainly renally eliminated and not an inhibitor of CYP450 enzymes in vitro. Glyburide, a sulphonylurea, is an insulin sensitizer and mainly metabolized by CYP2C9. Since both agents may potentially be co-administered, the purpose of this study was to examine the effects of sitagliptin on glyburide pharmacokinetics.

METHODS

In this open-label, randomized, two-period crossover study, eight healthy normoglycaemic subjects, 22–44 years old, received single 1.25-mg doses of glyburide alone in one period and co-administered with sitagliptin on day 5 following a multiple-dose regimen for sitagliptin (200-mg q.d. ×6 days) in the other period.

RESULTS

The geometric mean ratios and 90% confidence intervals [(glyburide + sitagliptin)/glyburide] for AUC_0–∞ and C_max were 1.09 (0.96, 1.24) and 1.01 (0.84, 1.23), respectively.

CONCLUSION

Sitagliptin does not alter the pharmacokinetics of glyburide in healthy subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• No data are available on the potential drug interaction of sitagliptin and glyburide.
• Sitagliptin belongs to a new class of drugs called DPP-4 inhibitors recently approved for the treatment of Type 2 diabetes.

WHAT THIS STUDY ADDS

• Glyburide is a commonly used sulphonylurea medication to treat Type 2 diabetes.
• Combination therapy is often required to achieve adequate glucose control in Type 2 diabetes.
• Sitagliptin does not appear to interfere with glyburide pharmacokinetics and therefore may be potentially co-administered with glyburide for the treatment of Type 2 diabetes.

     

Safety, tolerability and pharmacokinetics of udenafil, a novel PDE-5 inhibitor, in healthy young Korean subjects

AIM

To evaluate the safety, tolerability and pharmacokinetics (PK) of udenafil, a novel phosphodiesterase type 5 inhibitor.

METHODS

A double-blind, randomized, placebo-controlled, dose-rising, parallel-group, single- and multiple-dose study was conducted in healthy Korean subjects. The subjects were allocated to single-dose groups of 25, 50, 100, 200 or 300 mg (eight subjects in each dose group, including two placebos), or to multiple-dose groups of 100 or 200 mg (once-daily dosing for 7 days; nine subjects in each dose group, including three placebos). Serial samples of blood and urine were collected after oral administration and the drug concentrations in plasma and urine were determined by high-performance liquid chromatography. Safety and tolerability were evaluated by monitoring clinical laboratory parameters and adverse events.

RESULTS

Udenafil reached peak plasma concentrations at 0.8–1.3 h, and then declined mono-exponentially with a terminal half-life of 7.3–12.1 h in the single-dose study. The area under the time–concentration curves (AUC) and maximum plasma concentrations (C_max) increased supraproportionally with increasing dose in the single-dose study. During multiple dosing, a steady state was reached at 5 days and little accumulation occurred after repeated dosing for 7 days. Udenafil was generally well tolerated in these healthy subjects, and no serious adverse events occurred.

CONCLUSIONS

Udenafil was safe and well tolerated in healthy volunteers. The AUC and C_max of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The phosphodiesterase (PDE) type 5 inhibitor is a widely used agent that facilitates penile erection.
• Udenafil is newly developed as a PDE-5 inhibitor.

WHAT THIS STUDY ADDS

• This is the first study to determine the safety, tolerability and pharmacokinetics of udenafil in healthy subjects.
• Udenafil was safe and well tolerated in healthy Korean subjects.
• The AUC and C_max of udenafil increased supraproportionally with increasing dose upon single administration, but there was no significant drug accumulation upon multiple administrations.

     

Impact of noncompliance with alendronate and risedronate on the incidence of nonvertebral osteoporotic fractures in elderly women

AIMS

To evaluate the association between noncompliance with alendronate and risedronate and the risk of nonvertebral osteoporotic fracture in community-dwelling elderly women.

METHODS

A nested case–control study was conducted using the Quebec administrative health databases. To be included in the cohort, women needed to be aged ≥ 68 years and to have initiated treatment with alendronate or risedronate between 1 January 2002 and 31 March 2005. Cases consisted of all women with an incident nonvertebral osteoporotic fracture occurring ≥ 1 year after initiation of therapy. Each case was matched with up to 20 controls using incidence density sampling, according to age (± 1 year) and follow-up duration. A woman was noncompliant if she had a medication possession ratio (MPR) <80% for total follow-up duration. Rate ratios (RR) for fracture were estimated through conditional logistic regression analysis, adjusting for potential confounders.

RESULTS

Among the 30 259 women included in the cohort, 1036 nonvertebral fracture cases were identified and were matched to 20 069 controls. Compared with women with a MPR ≥ 80%, those with a MPR < 80% had a greater risk of nonvertebral fracture [adjusted RR 1.27, 95% confidence interval (CI) 1.12, 1.44]. Considering hip fracture only, the multivariate model yielded similar results, (adjusted RR 1.28, 95% CI 1.02, 1.61).

CONCLUSIONS

Among community-dwelling elderly women, noncompliance with alendronate or risedronate is associated with an increased risk of nonvertebral fracture.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Compliance with alendronate and risedronate is suboptimal.
• Few studies have specifically evaluated the impact of noncompliance with alendronate or risedronate on the incidence of osteoporotic fractures in community-dwelling elderly women.

WHAT THIS STUDY ADDS

• Among community-dwelling elderly women, noncompliance [defined as medication possession ratio (MPR) < 80%] with alendronate or risedronate was associated with a 27% increased risk of nonvertebral fracture [rate ratio (RR) 1.27, 95% confidence interval (CI) 1.12, 1.44].
• This study is the first to assess the impact of noncompliance with bisphosphonates in a subgroup of women aged > 80 years.
• Among women aged > 80 years, MPR < 80% was associated with a 48% greater risk of sustaining a nonvertebral fracture (RR 1.48, 95% CI 1.19, 1.85), compared with women with a MPR ≥ 80%.