Intra-individual Variability In Response Research Articles

Development of a vestibular schwannoma tumor slice model for pharmacological testing

BackgroundOur goal was to develop a 3D tumor slice model, replicating the individual tumor microenvironment and for individual pharmaceutical testing in vestibular schwannomas with and without relation to NF2. MethodsTissue samples from 16 VS patients (14 sporadic, 2 NF2-related) were prospectively analyzed. Slices of 350 µm thickness were cultured in vitro, and the 3D tumor slice model underwent thorough evaluation for culturing time, microenvironment characteristics, morphology, apoptosis, and proliferation rates. Common drugs - Lapatinib (10 µM), Nilotinib (20 µM), and Bevacizumab (10 µg/ml) - known for their responses in VS were used for treatment. Treatment responses were assessed using CC3 as an apoptosis marker and Ki67 as a proliferation marker. Standard 2D cell culture models of the same tumors served as controls. ResultsThe 3D tumor slice model accurately mimicked VS ex vivo, maintaining stability for three months. Cell count within the model was approximately tenfold higher than in standard cell culture, and the tumor microenvironment remained stable for 46 days. Pharmacological testing was feasible for up to three weeks, revealing interindividual differences in treatment response to Lapatinib and intraindividual variability in response to Lapatinib and Nilotinib. The observed effects were less pronounced in tumor slices than in standard cell culture, indicating the model's proximity to in vivo tumor biology and enhanced realism. Bevacizumab had limited impact in both models. ConclusionThis study introduces a 3D tumor slice model for sporadic and NF2-related VS, demonstrating stability for up to 3 months, replication of the schwannoma microenvironment, and utility for individualized pharmacological testing.

584-P: Similar Variability in Pre- and Post-exercise Glucose Levels between Morning-Fasted and Afternoon-Fed Resistance Exercise in Adults with Type 1 Diabetes

Background: Exercise increases longevity and decreases the incidence/progression of diabetes-related complications for those with type 1 diabetes (T1D), but it complicates blood glucose management. Understanding variability in blood glucose response to exercise may help guide choices of exercise strategies for people with T1D. Our primary objective was to compare the variability in capillary glucose (CG) response to morning, fasted resistance exercise (AMre), to afternoon post-prandial exercise (PMre). We hypothesized that CG responses would be less variable during morning fasted RE. Methods: Seven participants [4F/3M; mean (SD): age = 29.1 (11.3) yrs; diabetes duration = 19.4 (6.7) yrs; HbA1c = 7.5 (0.7)%] completed a standardized resistance exercise protocol (3 sets of 8 repetitions of seven exercises involving all major muscle groups with 90 seconds between sets) three times in the morning (~7am) while in a fasted state and three times in the afternoon (~5pm) in a fed state. Sessions were performed in a random order with at least 48 hrs between sessions. Participants aimed for close consistency in the timing of the sessions, any associated meals (PMre only) and related insulin adjustments. To determine the intra-individual variability in CG response during AMre and PMre, as well as subsequent 30-minute recovery periods, we performed paired t-tests of the within-participant SD of the change in CG. Results: From the beginning to the end of RE, mean within-participant SD of CG change was 1.2 (0.5) and 1.9 (1.2) mmol/L during AMre and PMre respectively (p=0.08), and 1.2 (0.4) and 1.2 (1.2) mmol/L during subsequent 30-minute recovery periods (p=0.98). Conclusion: For adults with T1D the variability in CG response may be similar between AMre and PMre. More data are needed to clarify these effects. Disclosure R.Mcclure: None. C.J.Nitz: None. J.E.Yardley: Speaker's Bureau; Dexcom, Inc., Abbott. Funding LifeScan

Linear Model Identification for Personalized Prediction and Control in Diabetes.

Type-1 diabetes (T1D) is a disease characterized by impaired blood glucose (BG) regulation, forcing patients to multiple daily therapeutic actions, including insulin administration. T1D management could considerably benefit of accurate BG predictions and automated insulin delivery. For both tasks, the large inter- and intra-individual variability in glucose response represents a major challenge. This work investigates different techniques to learn individualized linear models of glucose response to insulin and meal, suitable for model-based prediction and control. We focus on data-driven techniques for linear model-learning and compare the state-of-art parametric pipeline with a novel non-parametric approach based on Gaussian regression and Stable-Spline kernel. On data collected by 11 T1D individuals, the effectiveness of different models was evaluated by measuring root mean squared error (RMSE), coefficient of determination (COD), and time gain associated with BG predictors. Among the tested approaches, the non-parametric technique results in the best prediction performance: median RMSE = 29.8 mg/dL, and median COD = 57.4%, for a prediction horizon (PH) of 60 min. With respect to the state-of-the-art parametric techniques, the non-parametric approach grants a COD improvement of about 2%, 7%, 21%, and 41% for PH = 30, 60, 90, and 120 min (paired-sample t-test p ≤ 0.001, p = 0.003, p = 0.03, and p = 0.07 respectively). Non-parametric linear model-learning grants statistically significant improvement with respect to the state-of-art parametric approach. The higher PH, the more pronounced the improvement. The use of a linear non-parametric model-learning approach for model-based prediction and control could bring to a more prompt, safe and effective T1D management.

Variability in hemoglobin mass response to altitude training camps.

The present study investigated whether athletes can be classified as responders or non-responders based on their individual change in total hemoglobin mass (tHb-mass) following altitude training while also identifying the potential factors that may affect responsiveness to altitude exposure. Measurements were completed with 59 elite endurance athletes who participated in national team altitude training camps. Fifteen athletes participated in the altitude training camp at least twice. Total Hb-mass using a CO rebreathing method and other blood markers were measured before and after a total of 82 altitude training camps (1350-2500m) in 59 athletes. In 46 (56%) altitude training camps, tHb-mass increased. The amount of positive responses increased to 65% when only camps above 2000m were considered. From the fifteen athletes who participated in altitude training camps at least twice, 27% always had positive tHb-mass responses, 13% only negative responses, and 60% both positive and negative responses. Logistic regression analysis showed that altitude was the most significant factor explaining positive tHb-mass response. Furthermore, male athletes had greater tHb-mass response than female athletes. In endurance athletes, tHb-mass is likely to increase after altitude training given that hypoxic stimulus is appropriate. However, great inter- and intra-individual variability in tHb-mass response does not support classification of an athlete permanently as a responder or non-responder. This variability warrants efforts to control numerous factors affecting an athlete's response to each altitude training camp.

Work-matched High-intensity Interval And Moderate-intensity Continuous Training Adaptations On 17 Lactate Threshold Methods In Females

PURPOSE: to compare exercise training effects on 17 lactate threshold methods to 6 weeks (3x/week) of high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) in females. METHODS: 24 healthy sedentary females (mean ± SD: peak oxygen uptake 30.0 ± 3.2 mLᐧkg-1ᐧmin-1, peak power output 151 ± 21 W, body mass index 23.4 ± 2.6 kgᐧm-2) were randomly assigned to either HIIT or MICT. Participants performed a step-incremental test on a cycle ergometer (3-min stages of 25-W increments, starting at 25 W) pre- and post-training. The HIIT group (N = 12) performed a 10-min warm-up (power output (PO) at 70% of the maximal heart rate (HRmax)), and four 4-min intervals (PO at 90% HRmax) interspersed with 4-min recovery at 30 W. The MICT group (N = 12) performed 60-min continuous cycling (PO at 90% of the first lactate turning-point (LT1)). Lactate thresholds were analyzed as: Log-log, onset of blood lactate accumulation (OBLA, N = 5), fixed value above baseline (Bsln+, N = 3), Dmax and its modified versions (N = 5), lactate turning-points (LT1 and LT2), and the minimal lactate-intensity ratio (LTratio). A two-way analysis of variance was used to test differences within (post versus pre) and between groups. Additionally, the width of confidence intervals (CIwidth) from the delta change was calculated for each method and group. RESULTS: In the HIIT group, the intensity derived from all the methods significantly increased after training (p < 0.01), except for LTratio (p = 0.6). In the MICT group, the intensity from OBLA, Bsln+, and the modified Dmax methods significantly increased after training (p < 0.05), whereas Log-log, Dmax, LT1, LT2, and LTratio did not improve significantly (p > 0.05). The HIIT group showed a higher increase in intensity from the Dmax methods, and in LT1 and LT2 compared with the MICT group (p < 0.05). No differences were observed between the groups in the improvements of Log-log, OBLA, Bsln+, and LTratio. OBLA at 3.5 and 4.0 mM, and Dmax presented the narrowest CIwidth (range 7 - 12 W), while Bsln+ 0.5 mM, Bsln+ 1.0 mM, and Log-log had the widest CIwidth (range 24 - 32 W). CONCLUSIONS: In healthy sedentary females, improvements of the Dmax methods, LT1, and LT2 were superior in the HIIT group. The lowest intra-individual variability in response to training was observed in the Dmax and OBLA at 3.5 and 4.0 mM methods.

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5‐day repeated sessions study

Despite accumulating evidence of inter and intraindividual variability in response to theta burst stimulation, it is widely believed that in therapeutic applications, repeated sessions can have a "build-up" effect that increases the response over and above that seen in a single session. However, strong evidence for this is lacking. Therefore, we examined whether daily administration of intermittent theta burst stimulation (iTBS) over the primary motor cortex induces cumulative changes in transcranial magnetic stimulation measures of cortical excitability, above the changes induced by sham stimulation. Over five consecutive days, 20 healthy participants received either active iTBS or sham stimulation. Each day, baseline measures of cortical excitability were assessed before and up to 30min after the intervention. There was no significant difference in the rate of response between iTBS and sham stimulation on any of the 5days. There was no iTBS specific cumulative increase of corticospinal excitability. The likelihood that an individual would remain a responder from day-to-day was low in both groups, implying high within-subject variability of both active and sham iTBS after-effects. In contrast, we found a high within-subject repeatability of resting and active motor threshold, and baseline motor-evoked potential amplitude. In summary, sham stimulation has similar effect to active iTBS on corticospinal excitability, even when applied repeatedly for 5days. Our results might be relevant to research and clinical applications of theta burst stimulation protocols.

Trend Extraction in Functional Data of Amplitudes of R and T Waves in Exercise Electrocardiogram

The amplitudes of R and T waves of the electrocardiogram (ECG) recorded during the exercise test show both large inter- and intra-individual variability in response to stress. We analyze a dataset of 65 normal subjects undergoing ambulatory test. We model the dataset of R and T series in the framework of functional data, assuming that the individual series are realizations of a non-stationary process, centered at the population trend. We test the time variability of this trend computing a simultaneous confidence band and the zero crossing of its derivative. The analysis shows that the amplitudes of the R and T waves have opposite responses to stress, consisting respectively in a bump and a dip at the early recovery stage. Our findings support the existence of a relationship between R and T wave amplitudes and respectively diastolic and systolic ventricular volumes.

Psychobiological Factors Affecting Cortisol Variability in Human-Dog Dyads.

Stress responses within dyads are modulated by interactions such as mutual emotional support and conflict. We investigated dyadic psychobiological factors influencing intra-individual cortisol variability in response to different challenging situations by testing 132 owners and their dogs in a laboratory setting. Salivary cortisol was measured and questionnaires were used to assess owner and dog personality as well as owners' social attitudes towards the dog and towards other humans. We calculated the individual coefficient of variance of cortisol (iCV = sd/mean*100) over the different test situations as a parameter representing individual variability of cortisol concentration. We hypothesized that high cortisol variability indicates efficient and adaptive coping and a balanced individual and dyadic social performance. Female owners of male dogs had lower iCV than all other owner gender-dog sex combinations (F = 14.194, p<0.001), whereas owner Agreeableness (NEO-FFI) scaled positively with owner iCV (F = 4.981, p = 0.028). Dogs of owners high in Neuroticism (NEO-FFI) and of owners who were insecure-ambivalently attached to their dogs (FERT), had low iCV (F = 4.290, p = 0.041 and F = 5.948, p = 0.016), as had dogs of owners with human-directed separation anxiety (RSQ) or dogs of owners with a strong desire of independence (RSQ) (F = 7.661, p = 0.007 and F = 9.192, p = 0.003). We suggest that both owner and dog social characteristics influence dyadic cortisol variability, with the human partner being more influential than the dog. Our results support systemic approaches (i.e. considering the social context) in science and in counselling.

Recent Developments in the Use of Sodium Bicarbonate as an Ergogenic Aid.

This review examines the current status of sodium bicarbonate as an ergogenic aid. It builds on previous reviews in the area. Current research would suggest that as an ergogenic aid, a 300 mg·kg dose of NaHCO3 can improve high-intensity exercise, within a range of exercise modalities, such as a single bout of supramaximal exercise, high-intensity intermittent activity, and skill-based sports. In particular, these benefits seem to be present to a greater extent within trained individuals. Despite this, there appears to exist a high intraindividual variability in response to NaHCO3, and therefore, the ergogenic benefits may not be induced during every exercise bout. Current thinking also suggests that athletes need to individualize their ingestion timings to maximize peak pH or blood bicarbonate to effectively maximize the performance effect, and this may allow individuals to attain the ergogenic benefits of NaHCO3 more consistently.

Quantitative determination of the enantiomers of methadone in human plasma and saliva by chiral column chromatography coupled with mass spectrometric detection

Methadone is a potent lipophilic synthetic opioid that is effective in the treatment of cancer pain and perceived benefit in difficult pain control scenarios (especially in cases of neuropathic pain). The use of methadone in clinical practice is challenging however, due to the narrow therapeutic window and large inter- and intra-individual variability in therapeutic response. Quantitation of the enantiomers d- and l-methadone (d- and l-MTD) in plasma and saliva provides a basis for studying its pharmacokinetics in patients with cancer and for monitoring efficacy, toxicity and side-effects. This assay involves quantitation of the enantiomers of methadone using their respective deuterated internal standards, in plasma and saliva matrices with no impact of ion suppression in either matrix. The analytical recoveries of d- and l-MTD from the saliva collection devices (Salivette®) are optimised in this novel method with an accurate and simple extraction method employing dichloromethane. Optimal enantioselective separations were achieved using an α1-acid glycoprotein chiral stationary phase and triple quadrupole tandem mass spectrometer. Linearity was demonstrated over 0.05–1000µg/L for both enantiomers in plasma and in saliva with correlation coefficients greater than 0.998. The lower limit of quantitation (LLOQ) was determined to be 0.1µg/L in plasma and saliva for d- and l-MTD. Accuracy of the method ranges from 100% to 106% even at the LLOQ and total precision, expressed as the coefficient of variation, was between 0.2% and 4.4% for both analytes in both matrices. A simple one step extraction procedure resulted in recoveries greater than 95% for both analytes, at concentrations as low as 0.5µg/L, from the Salivette®. The validated method was applied successfully in 14 paired plasma and saliva samples obtained from adult patients with cancer pain receiving methadone.

Inter- and Intra-individual Variability in Response to Transcranial Direct Current Stimulation (tDCS) at Varying Current Intensities.

Translation of transcranial direct current stimulation (tDCS) from research to clinical practice is hindered by a lack of consensus on optimal stimulation parameters, significant inter-individual variability in response, and in sufficient intra-individual reliability data. Inter-individual differences in response to anodal tDCS at a range of current intensities were explored. Intra-individual reliability in response to anodal tDCS across two identical sessions was also investigated. Twenty-nine subjects participated in a crossover study. Anodal-tDCS using four different current intensities (0.2, 0.5, 1 and 2 mA), with an anode size of 16 cm2, was tested. The 0.5 mA condition was repeated to assess intra-individual variability. TMS was used to elicit 40 motor-evoked potentials (MEPs) before 10 min of tDCS, and 20 MEPs at four time-points over 30 min following tDCS. ANOVA revealed no main effect of TIME for all conditions except the first 0.5 mA condition, and no differences in response between the four current intensities. Cluster analysis identified two clusters for the 0.2 and 2 mA conditions only. Frequency distributions based on individual subject responses (excitatory, inhibitory or no response) to each condition indicate possible differential responses between individuals to different current intensities. Test-retest reliability was negligible (ICC(2,1) = -0.50). Significant inter-individual variability in response to tDCS across a range of current intensities was found. 2 mA and 0.2 mA tDCS were most effective at inducing a distinct response. Significant intra-individual variability in response to tDCS was also found. This has implications for interpreting results of single-session tDCS experiments.

Duration-dependent effects of the BDNF Val66Met polymorphism on anodal tDCS induced motor cortex plasticity in older adults: a group and individual perspective

The brain derived neurotrophic factor (BDNF) Val66Met polymorphism and stimulation duration are thought to play an important role in modulating motor cortex plasticity induced by non-invasive brain stimulation (NBS). In the present study we sought to determine whether these factors interact or exert independent effects in older adults. Fifty-four healthy older adults (mean age = 66.85 years) underwent two counterbalanced sessions of 1.5 mA anodal transcranial direct current stimulation (atDCS), applied over left M1 for either 10 or 20 min. Single pulse transcranial magnetic stimulation (TMS) was used to assess corticospinal excitability (CSE) before and every 5 min for 30 min following atDCS. On a group level, there was an interaction between stimulation duration and BDNF genotype, with Met carriers (n = 13) showing greater post-intervention potentiation of CSE compared to Val66Val homozygotes homozygotes (n = 37) following 20 min (p = 0.002) but not 10 min (p = 0.219) of stimulation. Moreover, Met carriers, but not Val/Val homozygotes, exhibited larger responses to TMS (p = 0.046) after 20 min atDCS, than following 10 min atDCS. On an individual level, two-step cluster analysis revealed a considerable degree of inter-individual variability, with under half of the total sample (42%) showing the expected potentiation of CSE in response to atDCS across both sessions. Intra-individual variability in response to different durations of atDCS was also apparent, with one-third of the total sample (34%) exhibiting LTP-like effects in one session but LTD-like effects in the other session. Both the inter-individual (p = 0.027) and intra-individual (p = 0.04) variability was associated with BDNF genotype. In older adults, the BDNF Val66Met polymorphism along with stimulation duration appears to play a role in modulating tDCS-induced motor cortex plasticity. The results may have implications for the design of NBS protocols for healthy and diseased aged populations.

Inter- and intra-individual variability in response to anodal tDCS at varying current densities

Inter- and intra-individual variability in response to anodal tDCS at varying current densities

Prediction of individual response to antidepressants and antipsychotics: an integrated concept

In both clinical trials and daily practice, there can be substantial inter- and even intraindividual variability in response--whether beneficial or adverse--to antidepressants and antipsychotic medications. So far, no tools have become available to predict the outcome of these treatments in specific patients. This is because the causes of such variability are often not known, and when they are, there is no way of predicting the effects of their various potential combinations in an individual. Given this background, this paper presents a conceptual framework for understanding known factors and their combinations so that eventually clinicians can better predict what medication(s) to select and at what dose they can optimize the outcome for a given individual. This framework is flexible enough to be readily adaptable as new information becomes available. The causes of variation in patient response are grouped into four categories: (i) genetics; (ii) age; (iii) disease; and (iv) environment (internal). Four cases of increasing complexity are used to illustrate the applicability of this framework in a clinically relevant way In addition, this paper reviews tools that the clinician can use to assess for and quantify such inter- and intraindividual variability. With the information gained, treatment can be adjusted to compensate for such variability, in order to optimize outcome. Finally, the limitations of existing antidepressant and antipsychotic therapy and the way they reduce current ability to predict response is discussed.

Optimization of anemia treatment in hemodialysis patients via reinforcement learning.

Anemia is a frequent comorbidity in hemodialysis patients that can be successfully treated by administering erythropoiesis-stimulating agents (ESAs). ESAs dosing is currently based on clinical protocols that often do not account for the high inter- and intra-individual variability in the patient's response. As a result, the hemoglobin level of some patients oscillates around the target range, which is associated with multiple risks and side-effects. This work proposes a methodology based on reinforcement learning (RL) to optimize ESA therapy. RL is a data-driven approach for solving sequential decision-making problems that are formulated as Markov decision processes (MDPs). Computing optimal drug administration strategies for chronic diseases is a sequential decision-making problem in which the goal is to find the best sequence of drug doses. MDPs are particularly suitable for modeling these problems due to their ability to capture the uncertainty associated with the outcome of the treatment and the stochastic nature of the underlying process. The RL algorithm employed in the proposed methodology is fitted Q iteration, which stands out for its ability to make an efficient use of data. The experiments reported here are based on a computational model that describes the effect of ESAs on the hemoglobin level. The performance of the proposed method is evaluated and compared with the well-known Q-learning algorithm and with a standard protocol. Simulation results show that the performance of Q-learning is substantially lower than FQI and the protocol. When comparing FQI and the protocol, FQI achieves an increment of 27.6% in the proportion of patients that are within the targeted range of hemoglobin during the period of treatment. In addition, the quantity of drug needed is reduced by 5.13%, which indicates a more efficient use of ESAs. Although prospective validation is required, promising results demonstrate the potential of RL to become an alternative to current protocols.

Pharmacogenetics of Antiplatelets and Anticoagulants: A Report on Clopidogrel, Warfarin and Dabigatran

Genetic polymorphisms are thought to contribute to the wide intraindividual variability in antiplatelet and anticoagulant drug response. Pharmacogenetics is the study of how genetic variants influence drug response and how the adoption of a more personalized approach in antiplatelet and anticoagulant therapy may help to minimize harmful drug effects and optimize care for individual patients. However, due to sometimes conflicting evidence, the uptake of pharmacogenetics in the clinical setting has been slow. In this article, we review the genetic mechanisms contributing to the variability in response to three commonly used and emerging antiplatelet and anticoagulant drug therapies, namely clopidogrel, warfarin and dabigatran. We will focus on common genetic variants that influence the absorption, metabolism and/or action of these agents, including CYP2C19 (*2, *3 and *17), CYP3A4, CYP3A5, CYP2C9, ABCB1, P2RY12, CYP2C9 (*2/*3), VKORC1 and CESI.

Monitoring of anticoagulant therapy applying a dynamic statistical model

Patients with an increased risk of thrombosis may require treatment with vitamin K-antagonists such as warfarin. Treatment with warfarin has been reported difficult mainly due to high inter- and intraindividual variability in response to the drug [1]. Using predictive models that can predict International Normalised Ratio (INR) values enables for a higher degree of individualised warfarin dosing regime. This paper reports the outcome of the development of a dynamic prediction model. It takes warfarin intake and INR values as inputs, and uses an individual sensitivity parameter to model response to warfarin intake. The model is set on state-space form and uses Kalman filtering technique to optimise individual parameters. Retrospective test of the model proved robustness to choices of initial parameters, and feasible prediction results of both INR values and suggested warfarin dosage, which may prove beneficial for both patients and healthcare takers.

Interstitial Lung Damage Due to Cocaine Abuse: Pathogenesis, Pharmacogenomics and Therapy

Medicinal agents, beside occupational and environmental agents, remain one of the most common causes for interstitial lung diseases (ILD). A major problem with ILD is the recognition of the causative agent. In some cases more or less characteristic features of presentation are described. Often, the connection between drug-use and the development of related inflammatory damage or idiosyncratic toxicities is hard to recognize and objectify. Cocaine, a xenobiotic and the most commonly used illicit drug, causes serious medical and social problems. An increasing incidence of lung toxicity related to cocaine or crack-use is being reported worldwide. However, the mechanism of the resulting lung injury is not fully understood. This review summarizes possible molecular mechanisms explaining intraindividual variability in cocaine response and lung toxicity. The importance of including pharmacogenomics in the work-up of patients with suspected drug-induced lung toxicity is highlighted.

Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement

AbstractManaging vitamin K antagonist (VKA) therapy is challenging in children because of a narrow therapeutic range and wide inter- and intra-individual variability in dose response. Only a few small studies have investigated the effect of nongenetic and genetic factors on the dose response to VKAs in children. In a cohort study including 118 children (median age 9 years; range, 3 months-18 years) mostly with cardiac disease, we evaluated by multivariate analysis the relative contribution of nongenetic factors and VKORC1/CYP2C9/CYP4F2 genotypes on warfarin (n = 83) or fluindione (n = 35) maintenance dose and the influence of these factors on the time spent within/above/below the range. The results showed that height, target international normalized ratio and VKORC1 and CYP2C9 genotypes were the main determinants of warfarin dose requirement, accounting for 48.1%, 4.4%, 18.2%, and 2.0% of variability, respectively, and explaining 69.7% of the variability. Our model predicted the warfarin dose within 7 mg/wk in 86.7% of patients. None of the covariates was associated with the time spent above or below the international normalized ratio range. Whether this model predicts accurately the effective maintenance dose is currently being investigated.

Development of Cocaine-Induced Interstitial Lung Damage in Two CYP2C and VKORC1 Variant Allele Carriers

Often, the connection between drug use and the development of related inflammatory damage or idiosyncratic toxicities is hard to recognize and objectify. The presence of cytochrome P450 (CYP) variant genotypes appears to be a substantial susceptibility risk factor in the development of drug-induced pulmonary adverse events. We hypothesized that the presence of variant alleles may be associated with serious complications of illicit drug use. We report the cases of two cocaine users who developed a 'flu-like' syndrome with diffuse interstitial infiltrates after cocaine abuse. Genotyping for CYP (CYP2C9, CYP2C19) and vitamin K epoxide reductase complex 1 (VKORC1) allelic variants (-1639G/A and 1173C/T) was performed in these two patients. Both cases were heterozygous for VKORC1 variant alleles, and both possessed a CYP2C polymorphism (case 1: CYP2C19*1/*2; case 2: CYP2C9*1/*3). The described drug abuse cases suggest that an association between the presence of CYP2C and VKORC1 allelic variants and cocaine-induced interstitial lung damage is highly likely. It is assumed that these polymorphisms contribute to intra-individual variability in drug response and toxicity, including cocaine response and toxicity. Moreover, the importance of including pharmacogenomics in the work-up of patients with suspected drug-induced (lung) toxicity, such as alveolar hemorrhage, is highlighted by these cases.