The influence of a digital clinical reasoning test on medical student learning behavior during clinical clerkships.

Recently, a new digital clinical reasoning test (DCRT) was developed to evaluate students' clinical-reasoning skills. Although an assessment tool may be soundly constructed, it may still prove inadequate in practice by failing to function as intended. Therefore, more insight is needed into the effects of the DCRT in practice. Individual semi-structured interviews and template analysis were used to collect and process qualitative data. The template, based on the interview guide, contained six themes: (1) DCRT itself, (2) test debriefing, (3) reflection, (4) practice/workplace, (5) DCRT versus practice and (6) 'other'. Thirteen students were interviewed. The DCRT encourages students to engage more in formal education, self-study and workplace learning during their clerkships, particularly for those who received insufficient results. Although the faculty emphasizes the different purposes of the DCRT (assessment of/as/for learning), most students perceive the DCRT as an assessment of learning. This affects their motivation and the role they assign to it in their learning process. Although students appreciate the debriefing and reflection report for improvement, they struggle to fill the identified knowledge gaps due to the timing of receiving their results. Some students are supported by the DCRT in exhibiting lifelong learning behavior. This study has identified several ways in which the DCRT influences students' learning practices in a way that can benefit their clinical-reasoning skills. Additionally, it stresses the importance of ensuring the alignment of theoretical principles with real-world practice, both in the development and utilization of assessment tools and their content. Further research is needed to investigate the long-term impact of the DCRT on young physicians' working practice.

Fall in prevalence of impaired awareness of hypoglycaemia in individuals with type 1 diabetes.

AIMS: Impaired awareness of hypoglycaemia (IAH) has been reported to affect up to a third of people with type 1 diabetes. Whether the increased use of sensor technology has changed its prevalence remains unknown. The aim of this study was to investigate the current prevalence of IAH and its change over time in a cohort of individuals with type 1 diabetes. METHODS: IAH was assessed using the modified Clarke questionnaire in adults with type 1 diabetes. Participants were recruited from the diabetes outpatient clinic from February 2020 through April 2021. The scores were compared to similar data collected during previous assessments in 2006, 2010 and 2016 respectively. RESULTS: A total of 488 individuals (51.2% male) with a mean (±SD) age of 51.3 ± 15.9 years, median [Q1-Q3] diabetes duration of 30 [16-40] years and mean HbA1c of 60 ± 12 mmol/mol (7.7 ± 1.1%) were included. Sensors were used by 85% of the study population. IAH was present among 78 (16.0%) participants, whereas 86 (17.6%) participants had a history of severe hypoglycaemia. By comparison, the prevalence of IAH equalled 32.5% in 2006, 32.3% in 2010 and 30.1% in 2016 (p for trend <0.001), while the proportion of individuals reporting severe hypoglycaemia equalled 21.2%, 46.7% and 49.8% respectively (p for trend 0.010). Comparing sequential assessments over time, the proportion of individuals with persistent IAH decreased from 74.0% and 63.6% between 2006 and 2016 to 32.5% in 2020. CONCLUSIONS: Among individuals with type 1 diabetes and high use of sensor technology, the current prevalence of IAH was 16%, about 50% lower as compared to previous years.

What is it like to organize a large-scale educational event for fellow students? A qualitative exploration of student participation in curriculum design.

BACKGROUND: Although students are increasingly involved in curriculum design, empirical research on practices of actual student participation is sparse. The purpose of this study is to explore the experiences of students who collaborated in the organizing committee of a large-scale educational event, the Radboud Student Conference (RSC), for fellow students. METHODS: We conducted three focus group interviews, in which 17 (bio) medical students of three different organizing teams shared their experiences regarding the organization of the large-scale teaching event. The analysis was conducted using thematic content analysis, in which the codes and codebook were constructed on the basis of the data. RESULTS: The following four themes were derived from the data. 1) Collaboration, which concentrated on fellow students, teachers who were involved as supervisors, and persons outside the organizing team such as caterers, educational support office members, lecturers, physicians and researchers. 2) Planning and division of labor, with students experiencing a mutual dependence and noticing a gradual improvement of their skills. 3) Freedom implies responsibility, which indicted that students experienced a significant freedom to develop the RSC week, but at the same time felt the responsibility to deliver a successful final week of the academic year. 4) Personal development, where students mentioned the opportunity to practice skills that differed from standard (bio) medical electives. CONCLUSIONS: We conclude that (bio) medical students are capable of bearing the responsibility to organize a large-scale educational event. Organizing the RSC was an educational experience in the form of cooperative and experiential learning which contributed to students' personal development. Organizing the event gave students both a sense of freedom and the responsibility to succeed. Supervision of faculty members seemed a prerequisite, and tended to be supportive rather than guiding.

Learning clinical reasoning in the workplace: a student perspective.

INTRODUCTION: Clinical reasoning is a core competency for every physician, as well as one of the most complex skills to learn. This study aims to provide insight into the perspective of learners by asking students about their own experiences with learning clinical reasoning throughout the medical Master's curriculum. METHODS: We adopted a constructivist approach to organise three semi-structured focus groups within the Master's curriculum at the medical school of the Radboud University Medical Center in Nijmegen (Netherlands) between August and December 2019. Analysis was performed through template analysis. RESULTS: The study included 18 participants who (1) defined and interpreted clinical reasoning, (2) assessed the teaching methods and (3) discussed how they used their context in order to learn and perform clinical reasoning during their clinical rotations. They referred to a variety of contexts, including the clinical environment and various actors within it (e.g. supervisors, peers and patients). CONCLUSION: With regard to the process by which medical students learn clinical reasoning in practice, this study stresses the importance of integrating context into the clinical reasoning process and the manner in which it is learnt. The full incorporation of the benefits of dialogue with the practice of clinical reasoning will require additional attention to educational interventions that empower students to (1) start conversations with their supervisors; (2) increase their engagement in peer and patient learning; (3) recognise bias and copy patterns in their learning process; and (4) embrace and propagate their role as boundary crossers.

Effect of Mexiletine on Muscle Stiffness in Patients With Nondystrophic Myotonia Evaluated Using Aggregated N-of-1 Trials.

Importance: In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. Objective: To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. Design, Setting, and Participants: A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. Interventions: Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. Main Outcomes and Measures: Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. Results: Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). Conclusions and Relevance: In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases. Trial Registration: ClinicalTrials.gov Identifier: NCT02045667.

Genetic determinants of impaired awareness of hypoglycemia in type 1 diabetes.

OBJECTIVE: It is likely that impaired awareness of hypoglycemia (IAH) and severe hypoglycemia are in part determined by genetic factors. The aim of this study was to investigate candidate genes for associations with IAH and severe hypoglycemia in a cohort of patients with type 1 diabetes. PARTICIPANTS AND METHODS: Consecutive patients with type 1 diabetes were genotyped for single-nucleotide polymorphisms in or near the genes for the ß1 and ß2 adrenergic receptor (ADRB1, ADRB2), SORCS1, and BNC2, and for the insertion/deletion polymorphism in the ACE gene. IAH and severe hypoglycemia were assessed using a validated questionnaire. RESULTS: Of 486 patients, 32.5% were classified as having IAH. The Arg16Gly polymorphism of ADRB2 was associated with IAH (odds ratio: 1.49, 95% confidence interval: 1.01-2.20, P=0.046) Gly16 (GG) versus carriers of the A allele. In a haplotype analysis, the association was the highest in patients with GG at position 16 and heterozygous at position 27 (odds ratio: 2.19, 95% confidence interval: 1.33-3.61, P=0.03). There were no associations between IAH and other genes, and none of the studied genes was associated with severe hypoglycemia. CONCLUSION: Genotypes at two variants of ADRB2 are associated with IAH. This association is comparable with the risk of classical risk factors for IAH.

Pharmacokinetic drug-drug interaction study between raltegravir and citalopram.

BACKGROUND: Depression is the most common mental health disorder among HIV-infected patients. When treating HIV-infected patients with a selective serotonin reuptake inhibitor (SSRI), potential drug-drug interactions with antiretroviral agents have to be taken into account. We investigated the two-way pharmacokinetic drug-drug interaction and tolerability of concomitant administration of the SSRI citalopram and the HIV-1 integrase inhibitor raltegravir in healthy volunteers. METHODS: An open-label, crossover, two-period trial was conducted in 24 healthy volunteers. Subjects received the following treatments: citalopram 20 mg once daily for 2 weeks followed by the combination with raltegravir 400 mg twice daily for 5 days and after a washout period raltegravir 400 mg twice daily for 5 days. Intensive steady-state pharmacokinetic blood sampling was performed. Geometric mean ratios (GMRs) of the combination versus the reference treatment and 90% CIs were calculated for the area under the plasma concentration-time curve (AUC). CYP2C19 genotyping was performed because it influences N-demethylation of citalopram to desmethylcitalopram. RESULTS: A total of 22 healthy volunteers completed the trial. GMRs (90% CI) were 1.00 (0.98, 1.03) for citalopram AUC0-24 h, 0.99 (0.88, 1.12) for desmethylcitalopram AUC0-24 h and 0.77 (0.50, 1.19) for raltegravir AUC0-12 h. Raltegravir plasma concentration 12 h after intake (C12 h) did not change with concomitant use of citalopram. Within each CYP2C19 phenotype subgroup the citalopram metabolite-to-parent ratio, which is a measure for metabolic enzyme activity, was not influenced by concomitant raltegravir use. CONCLUSIONS: Raltegravir does not influence the pharmacokinetics of citalopram and desmethylcitalopram. Citalopram did not change the pharmacokinetics of raltegravir in a clinically meaningful way. The combination was well tolerated and can be administered without dose adjustments. ClinicalTrials.gov NCT01978782.

Pharmacokinetic Drug-Drug Interaction Study Between Raltegravir and Atorvastatin 20 mg in Healthy Volunteers.

BACKGROUND: Dyslipidemia is highly prevalent among patients with HIV infection and contributes to an increased risk of cardiovascular disease. We investigated the influence of a frequently used statin, atorvastatin, on the pharmacokinetics of the HIV-integrase inhibitor raltegravir and vice versa. METHODS: Open-label, crossover 3-period phase I trial in 24 healthy volunteers. Subjects took raltegravir 400 mg two times a day for 7 days, atorvastatin 20 mg once a day for 7 days, and the combination of atorvastatin 20 mg once a day + raltegravir 400 mg two times a day for 7 days with 2-week washout periods in between. Intensive steady-state 12- and 24-hour pharmacokinetic blood sampling was performed. Geometric mean ratios of the test treatment (combination raltegravir + atorvastatin) versus the reference treatment (raltegravir or atorvastatin alone) and 90% confidence intervals were calculated for the area under the plasma concentration-time curve (AUC). Fasting lipid profiles were obtained to assess short-term lipid-lowering effect of atorvastatin with or without concomitant raltegravir use. RESULTS: Twenty-four healthy volunteers (11 males) were enrolled. All but 1 subject completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence interval) were 1.01 (0.68-1.51) for raltegravir AUC(0-12h) and 1.00 (0.90-1.11) for atorvastatin AUC(0-24h). The AUC(0-24h) metabolite-to-parent ratio for atorvastatin lactone, ortho-hydroxy, and para-hydroxy atorvastatin did not change during concomitant raltegravir use. The effect of atorvastatin on low-density lipoprotein cholesterol was not significantly different when combined with raltegravir versus atorvastatin alone (P = 0.638). CONCLUSIONS: Atorvastatin 20 mg has no clinically relevant effect on the pharmacokinetics of raltegravir and vice versa. The combination was well tolerated and can be administered without dose adjustments.

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol.

BACKGROUND: To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. METHODS/DESIGN: We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. DISCUSSION: The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02045667.

Effect of fosamprenavir/ritonavir on the pharmacokinetics of single-dose olanzapine in healthy volunteers.

Psychosis and other mental illnesses are common in HIV-infected patients. Olanzapine is one of the preferred antipsychotic agents for the treatment of schizophrenia. Olanzapine is primarily metabolised by CYP1A2 and uridine diphosphate glucuronosyltransferase (UGT). High-dose ritonavir has been shown to increase olanzapine elimination through induction of CYP1A2 and/or UGT, but the effect of low-dose ritonavir on olanzapine pharmacokinetics is unknown. Fosamprenavir is an HIV protease inhibitor that is boosted by low-dose ritonavir. To compensate for the induction of olanzapine metabolism by fosamprenavir/ritonavir, we hypothesised that a dose increase of olanzapine to 15 mg with fosamprenavir/ritonavir would lead to a similar area under the concentration-time curve (AUC) compared with olanzapine 10 mg alone. An open-label, randomised, two-period, cross-over, single-centre trial was conducted in 24 healthy volunteers. Subjects were randomised to one of the following treatments: (A) fosamprenavir/ritonavir 700/100 mg twice daily (b.i.d.) for 16 days with a single dose of olanzapine 15 mg on Day 13, a wash-out period of 31 days and a single dose of olanzapine 10 mg on Day 48; or (B) the same medication in reverse order. Twenty subjects completed the trial. The geometric mean ratios (90% CI) of olanzapine AUClast, maximum drug concentration (C(max)) and apparent elimination half-life (t(1/2)) when taken with fosamprenavir/ritonavir versus olanzapine alone were 1.00 (0.93-1.08), 1.32 (1.18-1.47) and 0.68 (0.63-0.74), respectively. Fosamprenavir/ritonavir 700/100 mg b.i.d. appeared to induce olanzapine metabolism. We therefore propose a 50% dosage increase of olanzapine when combining with a ritonavir-boosted protease inhibitor.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the HCV protease inhibitor boceprevir and the proton pump inhibitor omeprazole.

OBJECTIVES: Proton pump inhibitors (PPIs) can limit the solubility of concomitant drugs, which can lead to decreased absorption and exposure. Reduced efficacy can be a consequence and in the case of an antimicrobial agent this may contribute to development of resistance. Patients chronically infected with the hepatitis C virus can be treated with a boceprevir-containing regimen and it is relevant to know if interactions between PPIs and boceprevir exist. This study was designed to investigate the influence of a frequently used PPI, omeprazole, on the pharmacokinetics of boceprevir and vice versa. METHODS: In this open-label, three-period, randomized, cross-over, Phase I study, healthy subjects were randomly assigned to 40 mg of omeprazole once daily for 5 days, 800 mg of boceprevir three times daily for 5 days and 40 mg of omeprazole once daily + 800 mg of boceprevir three times daily for 5 days, or the same treatment in a different order. Every treatment was followed by a wash-out period. At day 5 of every treatment pharmacokinetic blood sampling was performed for 8 h after medication intake. ClinicalTrials.gov: NCT01470690. RESULTS: All 24 subjects (15 males) completed the study and no serious adverse events were reported. Geometric mean ratios (90% CI) of the area under the plasma concentration-time curve up to 8 h (AUC0-8) and maximum plasma concentration (Cmax) of boceprevir with omeprazole versus boceprevir alone were 0.92 (0.87-0.97) and 0.94 (0.86-1.02), respectively. For omeprazole these values were 1.06 (0.90-1.25) for AUC0-8 and 1.03 (0.85-1.26) for Cmax for the combination versus omeprazole alone. CONCLUSIONS: Omeprazole did not have a clinically significant effect on boceprevir exposure, and boceprevir did not affect omeprazole exposure.

Lack of a clinically significant drug-drug interaction in healthy volunteers between the hepatitis C virus protease inhibitor boceprevir and the HIV integrase inhibitor raltegravir.

BACKGROUND: Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are likely to use both HIV and HCV treatment. Drug-drug interactions have been demonstrated between boceprevir, an HCV protease inhibitor, and frequently prescribed antiretroviral drugs, such as efavirenz and boosted HIV protease inhibitors. Concomitant administration of boceprevir with these drugs should be avoided. This study was designed to investigate the absence of a drug-drug interaction between boceprevir and raltegravir, an HIV integrase inhibitor. METHODS: This was an open-label, randomized, 2-period, crossover phase 1 trial in 24 healthy volunteers. All subjects were randomly assigned to receive boceprevir 800 mg every 8 hours for 9 days plus a single dose of raltegravir 400 mg on day 10 followed by a washout period and a single dose of raltegravir 400 mg on day 38, or the same medication in reverse order. Blood samples for pharmacokinetics were collected and pharmacokinetic parameters were calculated. RESULTS: The geometric mean (GM) of raltegravir area under the concentration-time curve (AUC)(0-12h) and maximum plasma concentration (C(max)) for raltegravir + boceprevir vs raltegravir alone were 4.27 (95% confidence interval [CI], 3.22-5.66) vs 4.04 (95% CI, 3.09-5.28) mg * hour/L and 1.06 (95% CI, .76-1.49) vs 0.93 (95% CI, .70-1.23) mg/L, respectively. GM ratio estimates of raltegravir AUC(0-12h) and C(max) for raltegravir + boceprevir vs raltegravir alone were 1.04 (90% CI, .88-1.22) and 1.11 (90% CI, .91-1.36), respectively. The GM of boceprevir AUC(0-8h), C(max), and C(8h) were 5.45 (95% CI, 5.11-5.81) mg * hour/L, 1.88 (95% CI, 1.72-2.06) mg/L, and 0.09 (95% CI, .07-.11) mg/L, respectively. These data are comparable to those from historical controls. CONCLUSIONS: Due to the absence of a clinically significant drug interaction, raltegravir can be recommended for combined HIV/HCV treatment including boceprevir. CLINICAL TRIALS REGISTRATION: NCT01288417.

Effect of ginkgo biloba on the pharmacokinetics of raltegravir in healthy volunteers.

Medicinal herbs may cause clinically relevant drug interactions with antiretroviral agents. Ginkgo biloba extract is a popular herbal product among HIV-infected patients because of its positive effects on cognitive function. Raltegravir, an HIV integrase inhibitor, is increasingly being used as part of combined antiretroviral therapy. Clinical data on the potential inhibitory or inductive effect of ginkgo biloba on the pharmacokinetics of raltegravir were lacking, and concomitant use was not recommended. We studied the effect of ginkgo biloba extract on the pharmacokinetics of raltegravir in an open-label, randomized, two-period, crossover phase I trial in 18 healthy volunteers. Subjects were randomly assigned to a regimen of 120 mg of ginkgo biloba twice daily for 15 days plus a single dose of raltegravir (400 mg) on day 15, a washout period, and 400 mg of raltegravir on day 36 or the test and reference treatments in reverse order. Pharmacokinetic sampling of raltegravir was performed up to 12 h after intake on an empty stomach. All subjects (9 male) completed the trial, and no serious adverse events were reported. Geometric mean ratios (90% confidence intervals) of the area under the plasma concentration-time curve from dosing to infinity (AUC(0-∞)) and the maximum plasma concentration (C(max)) of raltegravir with ginkgo biloba versus raltegravir alone were 1.21 (0.93 to 1.58) and 1.44 (1.03 to 2.02). Ginkgo biloba did not reduce raltegravir exposure. The potential increase in the C(max) of raltegravir is probably of minor importance, given the large intersubject variability of raltegravir pharmacokinetics and its reported safety profile.

Effect of posaconazole on the pharmacokinetics of fosamprenavir and vice versa in healthy volunteers.

OBJECTIVES: To manage the interaction between fosamprenavir/ritonavir and posaconazole, we hypothesized that ritonavir can be replaced by posaconazole as an alternative booster of fosamprenavir with no significant influence on posaconazole pharmacokinetics. METHODS: This was an open-label, randomized, three period, cross-over, single-centre trial in 24 healthy volunteers. All subjects received the following three treatments for 10 days, separated by washout periods of 17 days: posaconazole 400 mg twice daily; fosamprenavir/ritonavir 700/100 mg twice daily; posaconazole 400 mg twice daily with fosamprenavir 700 mg twice daily. RESULTS: Twenty subjects completed the trial. Geometric mean ratios (GMR; +90% confidence interval) of posaconazole AUC and C(max) when taken with fosamprenavir versus posaconazole alone were 0.77 (0.68-0.87) and 0.79 (0.71-0.89), respectively. The GMRs of amprenavir AUC and C(max) when taken as fosamprenavir and posaconazole versus fosamprenavir/ritonavir were 0.35 (0.32-0.39) and 0.64 (0.55-0.76), respectively. No serious adverse events were reported during the trial. CONCLUSION: Unboosted fosamprenavir should not be used concomitantly with posaconazole.

Drug-drug interactions between raltegravir and pravastatin in healthy volunteers.

BACKGROUND: To evaluate the potential drug-drug interaction between raltegravir and pravastatin. METHODS: This was an open-label, randomized, 3-period, cross-over, single-centre trial in 24 healthy volunteers. Subjects received the following treatments: pravastatin 40 mg every day for 4 days, raltegravir 400 mg twice a day for 4 days, and pravastatin 40 mg every day + raltegravir 400 mg twice a day for 4 days. The treatments were separated by washout periods of 10 days. On day 4 of each treatment period, blood samples for pharmacokinetics were collected throughout a 24-hour period. RESULTS: Geometric mean ratios (90% confidence interval) for pravastatin + raltegravir versus pravastatin alone were 0.96 (0.83 to 1.11) for AUC0-24 and 1.04 (0.85 to 1.26) for Cmax. The mean low-density lipoprotein cholesterol decrease after 4 days of pravastatin was 0.42 mmol/L both in the presence and the absence of raltegravir. The geometric mean ratio (90% confidence interval) AUC0-12, Cmax, and C12 for raltegravir + pravastatin versus raltegravir alone were 1.13 (0.77 to 1.65), 1.31 (0.81 to 2.13), and 0.59 (0.39 to 0.88), respectively. CONCLUSIONS: Raltegravir did not influence the pharmacokinetics or the short-term lipid-lowering effects of pravastatin, whereas pravastatin increased the Cmax but decreased the C12 of raltegravir. The effects of pravastatin on raltegravir pharmacokinetics are not likely to be clinically relevant.

The Arg16Gly variant of the beta2-adrenergic receptor predisposes to hypoglycemia unawareness in type 1 diabetes mellitus.

Hypoglycemia unawareness has been linked to desensitization of the beta2-adrenergic receptor. Desensitization of the beta2-adrenergic receptor (ADRB2) is genetically determined by the Arg16Gly variant of this receptor. We tested the hypothesis that hypoglycemia unawareness is more common among patients homozygous for the Gly16 variant. We performed genotyping of the A265G (Arg16Gly) polymorphism in the ADRB2 gene in 85 patients with type 1 diabetes and classified them according to hypoglycemia awareness status. A total of 45 patients (53%) were homozygous for Gly16, 32 patients (38%) were heterozygous and eight patients (9%) were homozygous for Arg16. Hypoglycemia unawareness was 3.4-fold more common among patients homozygous for Gly16 than among patients with other variants of the Arg16Gly polymorphism (P=0.014). We conclude that patients with type 1 diabetes who carry two alleles of the Gly16 variant of ADRB2 are at increased risk of developing hypoglycemia unawareness. Future studies are required to confirm these results in larger, independent populations.

Preserved sensitivity to beta2-adrenergic receptor agonists in patients with type 1 diabetes mellitus and hypoglycemia unawareness.

BACKGROUND AND OBJECTIVE: Use of beta(2)-adrenergic receptor agonists has been advocated for the treatment of hypoglycemia unawareness in type 1 diabetes. In vitro, however, hypoglycemia unawareness has been associated with reduced beta(2)-adrenergic sensitivity. Therefore, in vivo sensitivity to beta(2)-adrenergic receptor agonist stimulation was compared between type 1 diabetic patients with and without hypoglycemia unawareness and nondiabetic controls. METHODS: Ten type 1 diabetic patients with hypoglycemia unawareness, 12 type 1 diabetic patients with intact hypoglycemic awareness, and 11 healthy controls were enrolled. beta(2)-Adrenergic sensitivity was determined by measuring the forearm vasodilator response to intraarterial infusion of salbutamol. Salbutamol was infused in six increasing doses ranging from 0.003 to 1.0 mug(1).min(-1).dl(-1). Forearm blood flow (FBF) was bilaterally measured by venous occlusion plethysmography. Diabetic patients received low-dose insulin before FBF measurements to ensure that experiments were carried out under normoglycemic conditions. RESULTS: At baseline, FBF was 1.9 +/- 0.3 ml(1).min(-1).dl(-1) in controls, 2.3 +/- 0.4 ml(1).min(-1).dl(-1) in patients with intact awareness, and 1.4 +/- 0.1 ml(1).min(-1).dl(-1) in patients with hypoglycemia unawareness (P = 0.048 vs. aware patients). In response to salbutamol, FBF increased 9.1-fold in controls, 8.0-fold in patients with intact awareness, and 10.7-fold in patients with hypoglycemia unawareness (P = NS). Heart rate increased in all groups due to systemic spillover of salbutamol but appeared blunted, considering a greater fall in mean arterial pressure in patients with hypoglycemia unawareness. CONCLUSIONS: Sensitivity to beta(2)-adrenergic receptor agonist stimulation is preserved in type 1 diabetic patients with hypoglycemia unawareness.

Effect of sex on the cardiovascular response to adrenaline in humans.

Cardiovascular responsiveness to stress conditions differs between men and women. It is not known to what extent this observation is explained by differences in the release of stress hormones like adrenaline, or by differences in the response to adrenaline. Therefore, we quantified the hemodynamic response to infusion of adrenaline (0.04, 0.06, and 0.08 microg x kg(-1) x min(-1) for 20 minutes each) in 8 healthy men and 8 healthy premenopausal women. Arterial plasma adrenaline levels were measured before and after infusion. Heart rate and intra-arterial blood pressure were monitored throughout the experiment. Arterial plasma adrenaline levels increased similarly in both sexes. There was a larger increase in systolic blood pressure in women compared with men (17.6 +/- 2.8 versus 5.1 +/- 3.1 mm Hg, P < 0.01). In contrast, men showed a larger increase in heart rate compared with women (20.3 +/- 1.4 versus 11.2 +/- 2.8 bpm, P < 0.01). In conclusion, these data suggest that the cardiovascular response to adrenaline is predominantly alpha-adrenergic in premenopausal women, and predominantly beta-adrenergic in age-matched men.