Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) methods for the therapeutic drug monitoring of cytotoxic anticancer drugs: An update.

In the era of precision medicine, there is increasing evidence that conventional cytotoxic agents may be suitable candidates for therapeutic drug monitoring (TDM)- guided drug dosage adjustments and patient's tailored personalization of non-selective chemotherapies. To that end, many liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) assays have been developed for the quantification of conventional cytotoxic anticancer chemotherapies, that have been comprehensively and critically reviewed. The use of stable isotopically labelled internal standards (IS) of cytotoxic drugs was strikingly uncommon, accounting for only 48 % of the methods found, although their use could possible to suitably circumvent patients' samples matrix effects variability. Furthermore, this approach would increase the reliability of cytotoxic drug quantification in highly multi-mediated cancer patients with complex fluctuating pathophysiological and clinical conditions. LC-MS/MS assays can accommodate multiplexed analyses of cytotoxic drugs with optimal selectivity and specificity as well as short analytical times and, when using stable-isotopically labelled IS for quantification, provide concentrations measurements with a high degree of certainty. However, there are still organisational, pharmacological, and medical constraints to tackle before TDM of cytotoxic drugs can be more largely adopted in the clinics for contributing to our ever-lasting quest to improve cancer treatment outcomes.

Early specialized care after a first unprovoked epileptic seizure.

A first seizure is a life-changing event with physical and psychological consequences. We aimed to assess the role of early comprehensive patient care after a first unprovoked seizure to improve diagnostic accuracy and follow-up adherence. From April 2011 to March 2012, patients presenting a first unprovoked epileptic seizure received standard patient care (SPC), i.e., a consultation in the ED, an EEG and a CT scan. The patients were notified of the follow-ups. We compared this protocol to subsequently acquired "early comprehensive patient care" (ECPC), which included a consultation by an epileptologist in the emergency department (ED), a routine or long-term monitoring electroencephalogram (LTM-EEG), magnetic resonance imaging and three follow-up consultations (3 weeks, 3 months, 12 months). 183 patients were included (113 ECPC, 70 SPC). LTM-EEG and MRI were performed in 51 and 85 %, respectively, of the patients in the ECPC group vs in 7 and 52 % of the patients in the SPC group (p < 0.001). A final diagnosis was obtained in 64 vs 43 % of the patients in the ECPC vs SPC group (p < 0.01). Patient attendance at 3-month was 84 % in the ECPC group vs 44 % in the SPC group (p < 0.001). At 12-month follow-up, the delay until the first recurrence was longer in the ECPC group (p = 0.008). An early epileptologist-driven protocol is associated with clinical benefit in terms of diagnostic accuracy, follow-up adherence and recurrence. This study highlights the need for epilepsy experts in the early assessment of a first epileptic seizure, starting already in the ED.

[Rethinking the reimbursement policy of direct acting antivirals against chronic hepatitis C]. / Repenser la politique de remboursement des agents antiviraux directs contre l'hépatite C chronique.

New direct-acting antivirals (DAA) against hepatitis C virus (HCV) have led to a therapeutic revolution in HCV management and virological cure rates approaching 100% while potentially avoiding significant complications of HCV (first cause of liver transplantation). We estimated the price of sustained virological response (SVR) depending on treatment strategy and patient profile. Costs of treatment with recent DAAs being so high, the accessibility to those drugs for the majority of subjects is hitherto limited to advanced stages of hepatitis C. This current situation increases the inequity and strengthens the dominant position of insurers and pharmaceutical companies with a rationing of care. We suggest herein global approaches from a population-level and health-care perspective aiming to reduce the prevalence, morbidity, and mortality related to HCV.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

[Psychiatric patients and QT interval monitoring]. / Surveillance de l'intervalle QT chez le patient psychiatrique.

Cardiovascular morbidity and mortality are higher in psychiatric patients than in the general population. In schizophrenic patients without cardiovascular history, long QT interval is a major risk factor for torsades de pointe and for sudden death. QT interval prolongation is a severe and underestimated dose-dependent adverse reaction triggered by several psychotropic drugs and by clinical situations such as polymedication, methadone maintenance treatment, electrolytic disturbances, cardiovascular history and congenital long QT syndromes. Systematic measurement of QT interval is recommended when psychotropic medications known to prolong it are introduced, as well as in clinical situations at risk. Stereoselective R-methadone administration (chiral switching) contributes to reduce the risk of QT prolongation.

[Antihypertensive therapy and drug-drug interactions]. / Traitement de l'hypertension artérielle et interactions médicamenteuses.

Adverse drug reactions (ADR) have increasing clinical implications and are a permanent challenge for general practitioners. Data suggest that ADR cause 3 to 18% of all hospital admissions with potentially serious consequences. Polymedication, female sex, multiple pathologies with age-related changes are predisposing factors. Antihypertensive drugs with a low bioavailability, a high protein binding capacity and specific elimination pathways are particularly prone to pharmacokinetic interactions. ACE-inhibitors, atenolol, moxonidine and diuretics have few pharmacokinetic interactions. Calcium channel blockers and beta-blockers are associated with an increased risk of pharmacokinetic drug-drug interactions. Diltiazem and verapamil are particularly prone to interactions, as they strongly inhibit the elimination of drugs undergoing the CYP3A4 and P-glycoprotein pathways.

[The selection of a drug in a defined therapeutic class: the case of the HMG-CoA reductase inhibitors]. / Sélection d'un medicament dans une classe thérapeutique donnée: l'exemple des "inhibiteurs de l'HMG-CoA reductase"

The HMG-CoA reductase inhibitors have similar therapeutic targets and indications. However, their potential pharmacokinetic drug-drug interaction profile may play a significant role in their safety profile in polymedicated and polymorbid patients and can serve as a selection criterion. If their utility is clearly demonstrated in selected conditions, their safety profile remains of concern. Beside dose-related hepatic and muscular injury, other rare and important adverse drug reactions have been reported after prolonged administration such as polyneuropathy, fibrotic interstitial pulmonary disease and lupus-like syndrome. Teratogenicity has also been associated with statin therapy.

Relationship between corneal temperature and finger temperature.

BACKGROUND: Because the temperature of the body surface depends largely on local blood flow, temperature measurements might provide information on the latter. OBJECTIVE: To evaluate the relationship between corneal temperature and finger temperature. METHODS: Corneal, finger, and body core temperatures were measured in a relatively unselected population of 266 white persons. Excluded were persons taking topical eye medication or with corneal inflammatory signs. Corneal and finger temperatures were measured on 1 randomly selected side of the body by means of a noncontact infrared thermometer. As a measure of body temperature, the tympanic temperature was measured by means of a noncontact infrared ear thermometer. A total of 124 females and 142 males were examined. RESULTS: A correlation analysis in a least squares regression model was highly significant (R = 0.67; P<.001), with corneal temperature as the dependent variable and environmental, tympanic, and finger temperatures and age and sex as predicting variables. All variables contributed significantly to prediction of the corneal temperature. The corrected mean corneal temperature after adjusting for environmental, tympanic, and finger temperatures and for age of participants was 0.16 degrees C higher in male participants (P = .002). CONCLUSIONS: Corneal temperature correlates with finger temperature even after adjusting for environmental and tympanic temperatures and for the age and sex of participants. A possible cause for these findings are some parallelisms in blood-flow regulation in the finger and the eye.