Increased frequency of CYP2C19 loss-of-function alleles in clopidogrel-treated patients with recurrent cerebral ischemia.

AIMS: Clopidogrel is used as secondary prevention after cerebral ischaemia. Previous, mainly Asian, studies have shown that genetic variations in CYP2C19 are associated with an increased risk of recurrent stroke in clopidogrel-treated patients. Evidence on the impact of this drug-gene interaction in European neurology patients is currently limited. The aim of this study is to compare the prevalence of CYP2C19 loss-of-function (LoF) alleles in a population with recurrent cerebral ischaemia to two reference groups from the same region. METHODS: CYP2C19-genotyping (*2 and *3) was performed in clopidogrel-treated patients who presented with a recurrent ischaemic stroke/transient ischaemic attack (TIA). Genotype distributions were compared with two reference groups; a cohort of consecutive patients who underwent elective coronary stent implantation and a cohort of healthy Dutch volunteers. RESULTS: In total, 188 cases with a recurrent ischaemic event were identified, of whom 38 (20.2%) experienced an early recurrent event (24 hours to 90 days after the previous event). Among the total case group, 43.6% of the patients carried at least one CYP2C19 LoF allele, compared with 27.6% and 24.7% in respectively the cardiology and the healthy volunteers reference groups (P < .001 for both comparisons). Among the cases with an early recurrent event, 55.3% of patients were carriers of at least one CYP2C19 LoF allele (P < .0001). CONCLUSION: In this clopidogrel-treated population with recurrent cerebral ischaemia, the frequency of CYP2C19 LoF alleles was significantly higher than in reference groups, especially in early recurrent events. This study adds to the growing body of evidence that genotype-guided antiplatelet therapy could improve patient outcomes.

Unintentional guideline deviations in hospitalized patients with two or more antithrombotic agents: an intervention study.

PURPOSE: Treatment schedules for antithrombotic therapy are complex, and there is a risk of inappropriate prescribing or continuation of antithrombotic therapy beyond the intended period of time. The primary aim of this study was to determine the frequency of unintentional guideline deviations in hospitalized patients. Secondary aims were to determine whether the frequency of unintentional guideline deviations decreased after intervention by a pharmacist, to determine the acceptance rate of the interventions and to determine the type of interventions. METHODS: We performed a non-controlled prospective intervention study in three teaching hospitals in the Netherlands. We examined whether hospitalized patients who used the combination of an anticoagulant plus at least one other antithrombotic agent had an unintentional guideline deviation. In these cases, the hospital pharmacist contacted the physician to assess whether this deviation was intentional. If the deviation was unintentional, a recommendation was provided how to adjust the antithrombotic regimen according to guideline recommendations. RESULTS: Of the 988 included patients, 407 patients had an unintentional guideline deviation (41.2%). After intervention, this was reduced to 22 patients (2.2%) (p < 0.001). The acceptance rate of the interventions was 96.6%. The most frequently performed interventions were discontinuation of an low molecular weight heparin in combination with a direct oral anticoagulant and discontinuation of an antiplatelet agent when there was no indication for the combination of an antiplatelet agent and an anticoagulant. CONCLUSION: A significant number of hospitalized patients who used an anticoagulant plus one other antithrombotic agent had an unintentional guideline deviation. Intervention by a pharmacist decreased unintentional guideline deviations.

Quality of clinical direct oral anticoagulant prescribing and identification of risk factors for inappropriate prescriptions.

AIMS: Even though the use of direct oral anticoagulants (DOACs) is safe based on clinical outcomes, drug safety also depends on appropriateness of drug prescription, which is challenging for DOACs since many patient factors need to be considered. The aim of this study was to assess the appropriateness of DOAC prescriptions and to identify risk factors of determinants for inappropriate DOAC prescriptions. METHODS: A retrospective study in a nonuniversity teaching hospital was performed of hospitalized patients (≥18 years) who received an initial DOAC prescription between February and August 2018. Appropriateness of prescribing was evaluated on 8 criteria by using a modified version of the medication appropriateness index. RESULTS: A total of 770 initial DOAC prescriptions of inpatients were evaluated: 267 patients (34.6%) had at least met 1 inappropriate criterion for a DOAC prescription. The most frequent inappropriate criterion was dosage (17.4%). Of the 4 DOACs, dabigatran (21.6%) and apixaban (21.2%) were mostly inappropriate dosed. In a multivariable analysis, reduced renal function (estimated glomerular filtration rate <50 mL/min; odds ratio [OR] = 2.35; P < .001), a diagnosis of atrial fibrillation (OR = 1.87; P = .004), and 'prescribed by surgeons' (OR = 1.9; P = .013) were independently associated with inappropriateness of prescribing. CONCLUSION: This study has highlighted a high degree of inappropriate prescribing of DOACs. These results underline the need for targeted interventions to improve DOAC prescribing.

Drug-Gene Risk Stratification in Patients with Suspected Drug-Induced Interstitial Lung Disease.

BACKGROUND: Pulmonary toxicity has been associated with drug use. This is often not recognized in clinical practice, and underestimated. OBJECTIVE: We aimed to establish whether polymorphisms in certain genes corresponding with a metabolic pathway of drug(s) used are associated with pulmonary toxicity in patients with suspected drug-induced interstitial lung disease (DI-ILD). METHODS: This retrospective observational study explored genetic variations in three clinically relevant cytochrome P450 (CYP) iso-enzymes (i.e., CYP2D6, CYP2C9, and CYP2C19) in a group of patients with a fibroticinterstitial lung disease, either non-specific interstitial pneumonia (n = 211) or idiopathic pulmonary fibrosis (n = 256), with a suspected drug-induced origin. RESULTS: Of the 467 patients, 79.0% showed one or more polymorphisms in the tested genes accompanied by the use of drug(s) metabolized by a corresponding affected metabolic pathway (60.0% poor metabolizers and/or using two or more drugs [likely DI-ILD], 37.5% using three or more [highly likely DI-ILD]). Most commonly used drugs were statins (63.1%) with a predominance among men (69.4 vs 47.1%, p < 0.0001). Nitrofurantoin, not metabolized by the tested pathways, was prescribed more frequently among women (51.9 vs 4.5%, p < 0.00001). CONCLUSIONS: In our cohort with suspected DI-ILD, 79% carried one or more genetic variants accompanied by the use of drugs metabolized by a corresponding affected pathway. In 60%, the diagnosis of DI-ILD was likely, whereas in 37.5%, it was highly likely, based on CYP analyses. This study underlines the importance of considering both drug use and genetic make-up as a possible cause, or at least a contributing factor, in the development and/or progression of fibrotic lung diseases. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00267800, registered in 2005.

The Clinical Implementation of CYP2C19 Genotyping in Patients with an Acute Coronary Syndrome: Insights From the FORCE-ACS Registry.

BACKGROUND: Guidelines recommend prasugrel or ticagrelor for acute coronary syndrome (ACS) patients. However, these P2Y12 inhibitors increase bleeding risk compared to clopidogrel. Although genotype-guided P2Y12-inhibitor selection has been shown to reduce bleeding risk, data on its clinical implementation is lacking. METHODS: The study included ACS patients receiving genotype-guided antiplatelet therapy, utilising either a point-of-care (POC) device or laboratory-based testing. We aimed to collect qualitative and quantitative data on genotyping, eligibility for de-escalation, physician adherence to genotype results, time to de-escalation and cost reduction. RESULTS: Of the 1,530 patients included in the ACS registry from 2021 to 2023, 738 ACS patients treated with ticagrelor received a CYP2C19 genotype test. The median turnover time of genotyping was 6.3 hours (interquartile range [IQR], 3.2-16.7), with 82.3% of the genotyping results known within 24 hours after admission. POC genotyping exhibited significantly shorter turnaround times compared to laboratory-based testing (with respective medians of 5.7 vs 47.8 hours; P < .001). Of the genotyped patients, 81.7% were eligible for de-escalation which was carried out within 24 hours in 70.9% and within 48 h in 93.0%. The time to de-escalation was significantly shorter using POC (25.4 hours) compared to laboratory-based testing (58.9 hours; P < .001). Implementing this strategy led to a reduction of €211,150.50 in medication costs. CONCLUSIONS: CYP2C19 genotype-guided-de-escalation in an all-comers ACS population is feasible. POC genotyping leads to shorter turnaround times and quicker de-escalation. Time to de-escalation from ticagrelor to clopidogrel in noncarriers was short, with high physician adherence to genotype results.

The influence of CYP2C19*2 and *17 on on-treatment platelet reactivity and bleeding events in patients undergoing elective coronary stenting.

OBJECTIVES: To investigate the impact of genotypes on the basis of the loss-of-function variant CYP2C19*2 and the gain-of-function variant CYP2C19*17 on on-treatment platelet reactivity and on the occurrence of Thrombolysis in Myocardial Infarction (TIMI) major bleedings in 820 clopidogrel-treated patients who underwent elective coronary stenting. METHODS: On-treatment platelet reactivity was quantified using ADP-induced light transmittance aggregometry (LTA) and the VerifyNow P2Y12 assay. Postdischarge TIMI major bleedings within 1 year after enrollment were recorded. RESULTS: In total, 25 major bleedings (3.0% of the study population) were observed. Patients with the CYP2C19*1/*17 and *17/*17 diplotypes exhibited a lower magnitude of platelet reactivity as compared with patients with the CYP2C19*1/*1 diplotype (for the light transmittance aggregometry-adjusted mean difference: -5.8%, 95% confidence interval: -9.6 to -2.1, P=0.002). Patients with the *1/*17 and *17/*17 genotype had a 2.7-fold increased risk in the occurrence of major bleedings [adjusted hazard ratio: 2.7, 95% confidence interval: 1.1-7.0, P=0.039]. The diplotypes *2/*17, *1/*2, and *2/*2 exhibited higher on-treatment platelet reactivity as compared with the wild type (P<0.0001). However, this was not translated into an altered risk on major bleedings as compared with the wild type [hazard ratio: 1.3 (0.45-4.0), P=0.60]. Results have not been adjusted for multiple testing. CONCLUSION: Patients with the CYP2C19*1/*17 and *17/*17 diplotype have a lower magnitude of on-treatment platelet reactivity and are at a 2.7-fold increased risk of postdischarge TIMI major bleeding events after coronary stenting than patients with the *1/*1 genotype. The diplotypes *2/*17, *1/*2, and *2/*2 are associated with increased on-treatment platelet reactivity; however, this is not translated into a lower risk of bleeding events.

The effect of low-dose aspirin on platelet function during pregnancy compared to placebo: An explorative study.

OBJECTIVES: To evaluate the effect of aspirin 80 mg compared to placebo on platelet function tests in the second and third trimester of pregnancy. STUDY DESIGN: An explorative study was performed to assess laboratory platelet function in a subpopulation of the APRIL trial: a randomized double-blind trial comparing aspirin 80 mg once daily to placebo for the prevention of recurrent preterm birth. Platelet function was measured between 18 and 22, and between 28 and 32 weeks gestational age with three platelet function tests: VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2). Medication adherence was evaluated by pill counts, self-reported diaries and structured interviews. RESULTS: We included 11 women, six in the aspirin and five in the placebo group. In women receiving aspirin, platelet function was significantly lower compared to women receiving placebo for all three tests: VerifyNow® Aspirin Reaction Units (450.5 vs 648.0, p = 0.017); Chronolog LTA (9.5% vs 94.5%, p = 0.009); serum TxB2 levels (11.9 ng/mL versus 175.9 ng/mL, p = 0.030). For all three tests, platelet function did not differ between the second and third trimester of pregnancy in the aspirin group. In the placebo group, serum TxB2 levels were significantly higher in the third trimester. One non-adherent participant in the aspirin group showed results similar to the placebo group. CONCLUSION: Aspirin 80 mg has a clear inhibitory effect on laboratory platelet function during pregnancy compared to placebo. This effect is similar in the second and third trimester of pregnancy.

Sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients.

Clopidogrel is a prodrug that needs to be converted in?vivo by several cytochrome (CYP) P450 iso-enzymes to become active. Both clopidogrel and the oral hypoglycemic drug class sulfonylureas are metabolized by the iso-enzyme CYP2C9. The objective of the study was to evaluate the relationship of sulfonylureas and on-clopidogrel platelet reactivity in type 2 diabetes mellitus patients undergoing elective coronary stent implantation. In this prospective, observational study, on-clopidogrel platelet reactivity was quantified using adenosine diphosphate (ADP)-induced light transmittance aggregometry in 139 type 2 diabetes mellitus patients undergoing elective coronary stent implantation treated with clopidogrel and aspirin. High on-clopidogrel platelet reactivity was defined as >70.7% platelet reactivity to 20 µmol/L ADP. A total of 53 patients (38.1%) were on concomitant treatment with sulfonylureas. The remaining 86 patients were on other hypoglycemic drugs. On-clopidogrel platelet reactivity was significantly higher in patients with concomitant sulfonylurea treatment as compared to patients without concomitant sulfonylurea treatment (for 5 µmol/L ADP: 46.0% ± 11.8 vs. 40.6% ± 16.0; p=0.035, adjusted p=0.032 and for 20 µmol/L ADP: 64.6% ± 10.8 vs. 58.7% ± 15.5; p=0.019, adjusted p=0.017). The concomitant use of sulfonylureas was associated with a 2.2-fold increased risk of high on-clopidogrel platelet reactivity (OR 2.2, 95% CI 1.1-4.7, p=0.039 and after adjustment for confounders: OR(adj) 2.0, 95% CI 1.0-5.7, p=0.048). Concomitant treatment with sulfonylureas might be associated with decreased platelet inhibition by clopidogrel in type 2 diabetes mellitus patients on dual antiplatelet therapy undergoing elective coronary stent implantation.

CYP2C19*2 and CYP2C9*3 alleles are associated with stent thrombosis: a case-control study.

AIMS: despite treatment with clopidogrel on top of aspirin, stent thrombosis (ST) still occurs being the most serious complication after percutaneous coronary interventions (PCIs). In this study, we aimed to determine the effect of variations in genes involved in the absorption (ABCB1 C1236T, G2677T/A, C3435T), metabolism (CYP2C19*2 and *3, CYP2C9*2 and *3, CYP3A4*1B and CYP3A5*3), and pharmacodynamics (P2Y1 A1622G) of clopidogrel on the occurrence of ST. METHODS AND RESULTS: the selected genetic variants were assessed in 176 subjects who developed ST while on dual antiplatelet therapy with aspirin and clopidogrel and in 420 control subjects who did not develop adverse cardiovascular events, including ST, within 1 year after stenting. The timing of the definite ST was acute in 66, subacute in 87, and late in 23 cases. The presence of the CYP2C19*2 and CYP2C9*3 variant alleles was significantly associated with ST (OR(adj): 1.7, 95% CI: 1.0-2.6, P = 0.018 and OR(adj): 2.4, 95% CI: 1.0-5.5, P = 0.043, respectively). The influence of CYP2C19*2 (OR(adj): 2.5, 95% CI: 1.1-5.5, P = 0.026) and CYP2C9*3 (OR(adj): 3.3, 95% CI: 1.1-9.9, P = 0.031) was most strongly associated with subacute ST. No significant associations of the other genetic variations and the occurrence of ST were found. CONCLUSION: carriage of the loss-of-function alleles CYP2C19*2 and CYP2C9*3 increases the risk on ST after PCI.

Role of Drug-Gene Interactions and Pharmacogenetics in Simvastatin-Associated Pulmonary Toxicity.

INTRODUCTION: Simvastatin has previously been associated with drug-induced interstitial lung disease. In this retrospective observational study, cases with non-specific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (IPF) with simvastatin-associated pulmonary toxicity (n = 34) were evaluated. OBJECTIVE: To identify whether variations in genes encoding cytochrome P450 (CYP) enzymes or in the SLCO1B1 gene (Solute Carrier Organic anion transporting polypeptide 1B1 gene, encoding the organic anion transporting polypeptide 1B1 [OATP1B1] drug transporter enzyme), and/or characteristics of concomitantly used drugs, predispose patients to simvastatin-associated pulmonary toxicity. METHODS: Characteristics of concomitantly used drugs and/or variations in the CYP or SLCO1B1 genes and drug-gene interactions were assessed. The outcome after withdrawal of simvastatin and/or switch to another statin was assessed after 6 months. RESULTS: Multiple drug use involving either substrates and/or inhibitors of CYP3A4 and/or three or more drugs with the potential to cause acidosis explained the simvastatin-associated toxicity in 70.5% (n = 24) of cases. Cases did not differ significantly from controls regarding CYP3A4, CYP2C9, or OATP1B1 phenotypes, and genetic variation explained only 20.6% (n = 7) of cases. Withdrawal of simvastatin without switching to another statin or with a switch to a hydrophilic statin led to improvement or stabilization in all NSIP cases, whereas all cases who were switched to the lipophilic atorvastatin progressed. CONCLUSION: Simvastatin-associated pulmonary toxicity is multifactorial. For patients with this drug-induced pulmonary toxicity who need to continue taking a statin, switching to a hydrophilic statin should be considered. CLINICALTRIALS. GOV IDENTIFIER: NCT00267800, registered in 2005.

Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation.

Context High on-treatment platelet reactivity is associated with atherothrombotic events following coronary stent implantation. Objective To evaluate the capability of multiple platelet function tests to predict clinical outcome. Design, Setting, and Patients Prospective, observational, single-center cohort study of 1069 consecutive patients taking clopidogrel undergoing elective coronary stent implantation between December 2005 and December 2007. On-treatment platelet reactivity was measured in parallel by light transmittance aggregometry, Verify Now P2Y12 and Platelet works assays, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/adenosine diphosphate (ADP) cartridge and Innovance PFA P2Y). Cutoff values for high on-treatment platelet reactivity were established by receiver operating characteristic curve (ROC) analysis. Main Outcome Measurement The primary end point was defined as a composite of all-cause death, nonfatal acute myocardial infarction, stent thrombosis, and ischemic stroke. The primary safety end point included TIMI (Thrombolysis In Myocardial Infarction) criteria major and minor bleeding. Results Kaplan-Meier analysis demonstrated that at 1-year follow-up, the primary end point occurred more frequently in patients with high on-treatment platelet reactivity when assessed by light transmittance aggregometry (52 [11.7%; 95% confidence interval {CI}, 8.9%-15.0%] vs 36 [6.0%;95%CI, 4.2%-8.2%] P.001; n=1049),Verify Now (54 [13.3%; 95% CI, 10.2%-17.0%] vs 37 [5.7%; 95% CI, 4.1%-7.8%]P.001; n=1052), Platelet works (33 [12.6%; 95% CI, 8.8%-17.2%] vs 21 [6.1%;95% CI, 3.8%-9.2%] P=.005; n=606), and Innovance PFA P2Y (18 [12.2%; 95%CI; 7.4%-18.6%] vs 28 [6.3%; 95% CI, 4.3%-8.9%] P=.02; n=588). ROC-curve analysis demonstrated that light transmittance aggregometry (area under the curve[AUC], 0.63; 95% CI, 0.58-0.68), Verify Now (AUC, 0.62; 95% CI, 0.57-0.67), and Platelet works (AUC, 0.61; 95% CI, 0.53-0.69) had modest ability to discriminate between patients with and without primary end point at 1-year follow-up. The IMPACT-R(n=905) and the Siemens PFA Collagen/ADP (n=812) were unable to discriminate between patients with and without the primary end point at 1-year follow-up (all AUCs included 0.50 in the CI). None of the tests identified patients at risk for bleeding. Conclusions Of the platelet function tests assessed, light transmittance aggregometry,Verify Now, Platelet works, and Innovance PFA P2Y were significantly associated with the primary end point. However, the predictive accuracy of these 4 tests was only modest. None of the tests provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation. Trial Registration clinical trials.gov Identifier: NCT00352014 [corrected].

[A poisonous spring smoothie with wild herbs: accidental intoxication with foxglove (Digitalis purpurea)]. / Een giftige lente-smoothie van wilde kruiden.

BACKGROUND: At a time when self-sufficiency and health are becoming increasingly important in society, the chances of intoxications with wild plants are increasing. Foxglove contains poisonous cardiac glycosides such as digoxin, digitoxin and gitoxin. The levels vary greatly and depend on the season and the location of the plants. The "non-digoxin" cardiac glycosides show a limited cross-reaction with the digoxin assay. This means that a low or therapeutic digoxin level does not rule out a severe foxglove intoxication. Due to the long half-life of the different cardiac glycosides, toxic symptoms can be persistent. CASE DESCRIPTION: A 43-year-old woman arrived at the Emergency Department with persistent vomiting and specific ECG-abnormalities. The day before, she drunk a smoothie made from wild plants picked in the woods. Patient appeared to have mistaken foxglove for common sorrel. CONCLUSION: In case of persistent gastrointestinal complaints with specific ECG abnormalities after ingestion of plant material, clinicians should be aware of a foxglove intoxication.

Resistance of aspirin during and after pregnancy: A longitudinal cohort study.

OBJECTIVES: The objective of this study is to investigate possible changes in aspirin resistance during and after pregnancy over time. STUDY DESIGN: A longitudinal cohort study in obstetric high risk women with an indication for aspirin usage during pregnancy to prevent placenta mediated pregnancy complications. MAIN OUTCOME MEASURES: Aspirin resistance measured in the first, second and third trimester of pregnancy and at least three months postpartum by four complementary test: PFA-200, VerifyNow®, Chronolog light transmission aggregometry (Chronolog LTA) and serum thromboxane B2 (TxB2) level measurements. Correlation between the devices was investigated. RESULTS: In total, 23 pregnant women participated in the present study. Aspirin resistance according to the PFA-200, VerifyNow®, Chronolog LTA and serum TxB2, was 30.4%, 17.4%, 26.1% and 23.8% respectively. Resistance by any device was 69.6%. Aspirin resistance measured by the VerifyNow®, Chronolog LTA, serum TxB2 and aspirin resistance by any device during pregnancy was demonstrated more frequently than aspirin resistance after pregnancy. Correlation between the different devices was weak. CONCLUSION: Aspirin resistance was found in a considerable part of the participants. Considerable variation between participants, within participants over time and between the different devices was found. Prevalence of aspirin resistance during pregnancy differs from after pregnancy. More research on aspirin resistance and clinical obstetric outcome is needed.

Severe pancytopenia and aspergillosis caused by thioguanine in a thiopurine S-methyltransferase deficient patient: a case report.

Azathioprine and mercaptopurine are widely used in the treatment of inflammatory bowel disease. However, its use is limited by adverse drug event related to the relatively narrow therapeutic index of the active metabolites. Several patients discontinue treatment because of intolerable adverse events or toxicity such as leucopenia and hepatotoxicity. High 6-thioguanine nucleotides and 6-methylmercaptopurine ribonucleotides levels are associated with toxicity. Variations in the thiopurine S-methyltransferase (TPMT) gene can lead to diminished TPMT enzyme activity and to an increased incidence of myelotoxicity due to high 6-methylmercaptopurine ribonucleotides levels after treatment with azathioprine and mercaptopurine. Unlike azathioprine and mercaptopurine, thioguanine is more directly metabolized to the active metabolites without formation of the toxic 6-methylmercaptopurine ribonucleotides. Taking this into account, it seems likely that thioguanine is less associated with myelotoxicity due to TPMT deficiency. However, we report the case of a Crohn's disease patient with life-threatening complications on 6TG treatment due to TPMT deficiency. Our patient developed a severe pancytopenia on thioguanine therapy, with 6-thioguanine nucleotides levels more than 10 times higher than the upper limit of the therapeutic window and was found to be a TPMT poor metabolizer (TPMT *3A/*3A). This case strongly illustrates that knowledge of TPMT enzyme activity is very important in the use of all thiopurines, including thioguanine. In conclusion, clinicians should be aware of the impact of TPMT deficiency on the metabolism of thioguanine and should consider performing preemptive TPMT genotyping in combination with frequent blood test monitoring when using thiopurines in general.

Effect of oxybutynin on exercise-induced sweating in healthy individuals.

OBJECTIVES: Oxybutynin has been proven to be effective in patients with generalized hyperhidrosis. Some dermatoses aggravate as a result of sweating. Therefore, oxybutynin might also be useful in such normohidrotic patients. The aim was to evaluate the efficacy and safety of different doses of oxybutynin on exercise-induced sweating in healthy individuals. METHODS: Two randomized, double-blind, placebo-controlled, cross-over studies were performed, in which two different dosages (2.5 and 5 mg) of oxybutynin were tested. The degree of sweating was determined by transepidermal water loss (TEWL) measurement on the forearm and the hand during exercise. Furthermore, the effectiveness was evaluated by means of the individual's global assessment score, and side effects were noted. RESULTS: No significant differences between oxybutynin and placebo were found on the forearm and the hand at both dosages of oxybutynin with respect to TEWL values and the individual's global assessment score. Side effects consisted of diarrhoea, dizziness, dry mouth and dry eyes. CONCLUSIONS: In this model, oxybutynin did not result in inhibition of exercise-induced sweating in healthy volunteers.

Systematic review of drug effects in humans and models with surfactant-processing disease.

Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky-Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations.We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation. In total, 73 articles were selected, consisting of 55 interstitial lung disease case reports/series, two clinical trials and 16 cell or mouse studies. Clinical effect parameters included lung function, radiological characteristics and clinical symptoms, while experimental outcome parameters included chemokine/cytokine expression, surfactant trafficking, necrosis and apoptosis. SP600125, a c-jun N-terminal kinase (JNK) inhibitor, hydroxychloroquine and 4-phenylbutyric acid were most frequently studied in disease models and lead to variable outcomes, suggesting that outcome is mutation dependent.This systematic review summarises effect parameters for future studies on surfactant-processing disorders in disease models and provides directions for future trials in affected patients.

Post-pregnancy aspirin resistance appears not to be related with recurrent hypertensive disorders of pregnancy.

OBJECTIVE: The FRUIT-RCT concluded that low-molecular-weight heparin added to aspirin compared to treatment with aspirin alone is beneficial in the prevention of early-onset hypertensive disorders of pregnancy (HD) in women with inheritable thrombophilia and prior HD and/or a small-for-gestational age (SGA) infant leading to delivery before 34 weeks gestation. The aim of this study is to answer the question whether aspirin resistance is associated with recurrent HD. STUDY DESIGN: Women with and without recurrent HD matched for age, study arm, and chronic hypertension were invited for this follow-up study 6-16 years after they participated in the FRUIT-RCT. Aspirin resistance was tested after 10days of aspirin intake using three complementary tests: PFA-200, VerifyNow® and serum thromboxane B2 (TXB2). An independent t-test, Mann-Whitney U test, Fisher's Exact test and Chi2 test were used for the statistical analyses. RESULTS: Thirteen of 24 women with recurrent HD and 16 of 24 women without recurrent HD participated. The prevalence of laboratory aspirin resistance was 34.5% according to the PFA-200, 3.4% according to the VerifyNow® and 24.1% according to TXB2. The prevalence of aspirin resistance by any test was 51.7%. Aspirin resistance per individual test did not differ between women with and without recurrent HD. Aspirin resistance measured by any test occurred more frequently in women without recurrent HD (p<0.01), irrespective of low-molecular-weight heparin. CONCLUSIONS: No relation could be demonstrated between recurrent HD and aspirin resistance per test, measured up to 16 years after pregnancy. On the contrary, complementary aspirin resistance measurements were encountered more frequently in women without recurrent HD.

[Anaphylaxis after iron dextran administration in a pregnant woman]. / Anafylaxie na ijzerdextraan bij een zwangere vrouw.

BACKGROUND: Iron deficiency is a frequent cause of anaemia in pregnancy and often results in fatigue and malaise. To prevent complications during labour, timely iron suppletion is important. CASE DESCRIPTION: A 30-year-old multiparous female presented at the outpatient clinic in her 38th week of this pregnancy because of fatigue and lightheadedness. She had been prescribed oral iron suppletion a month earlier but had not taken the tablets. Because her haemoglobin level had decreased to 6.3 mmol/l, it was decided to start her on intravenous iron dextran treatment. During administration of the test dose, the patient experienced acute dyspnoea and severe abdominal and back pain. Foetal bradycardia was observed and the patient underwent an emergency caesarean section. She delivered a healthy boy whose arterial pH was 7.05 (base excess: -7.6 mmol/l) and venous pH was 7.18 (base excess: -6.8 mmol/l). CONCLUSION: This case demonstrates that dextran anaphylaxis can occur, with potentially lethal consequences, even when no known underlying risk factors are present.