Caffeinated energy drinks in the Canadian context: health risk assessment with a focus on cardiovascular effects.

In Canada, caffeinated energy drinks (CEDs) currently sold under Temporary Marketing Authorizations must meet strict eligibility criteria. These criteria, which include compositional and labelling requirements, were developed based on the outcome of a health risk assessment conducted by Health Canada (HC) in 2013. HC updated its assessment by reviewing new information with the focus on potential cardiovascular effects associated with the consumption of CEDs available for sale in Canada. Due to limited data on CED consumption among Canadians to derive accurate exposure information, the composition of a typical CED was characterized to assess the potential effects of single ingredients and synergistic interactions between ingredients on the cardiovascular system. Surveillance data on potential adverse effects related to CED consumption was also analyzed. After extensive review, HC's updated assessment confirms the current risk management approach for CEDs is health protective for Canadian consumers, including the potential for cardiovascular effects. The available evidence supports that moderate consumption (up to 500 mL per day) of a typical CED authorized for sale in Canada is safe for the general population of healthy adults and adolescents. It also re-confirms that vulnerable sub-populations (i.e., children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals) should not consume CEDs. Novelty: Consumption up to 500 mL per day of a typical CED is not associated with an increased risk of cardiovascular effects. Children, pregnant and/or breastfeeding women, and caffeine-sensitive individuals should not consume CEDs.

A case of allergic contact dermatitis caused by Olanedine solution-A diagnostic patch-testing method involving dried filter paper.

BACKGROUND: Olanedine solution is a new antiseptic, and several cases of allergic contact dermatitis caused by the agent were reported in 2018; however, these cases were diagnosed based on positive results in 2-day closed patch testing of Olanedine solution "as is." OBJECTIVES: To present another case of Olanedine-induced allergic contact dermatitis and to analyze the optimal patch-testing method for this condition. METHODS: A 34-year-old Japanese female patient and 25 healthy control subjects were patch tested using wet filter paper, which had been treated with 15 µL Olanedine solution, and dried filter paper, which had been treated with 15 µL Olanedine solution and then dried. RESULTS: The patient and all of the control subjects exhibited false-positive reactions due to irritation in the 2-day closed patch tests with wet filter paper containing Olanedine solution "as is." The tests with dried filter paper produced a positive reaction on day 7 in the patient, and negative reactions in all control subjects. CONCLUSIONS: It is preferable to perform 2-day closed patch tests using filter paper with the test solution "as is," which had been dried before application in order to correctly diagnose antiseptic-induced allergic contact dermatitis.

Clinical benefits and pharmacology of scutellarin: A comprehensive review.

Stroke and myocardial infarction are among the most common causes of mortality and disability in the world. The ischemic injury underlying these illnesses is complex, involving intricate interplays among many biological functions including energy metabolism, vascular regulation, hemodynamics, oxidative stress, inflammation, platelet activation, and tissue repair that take place in a context- and time-dependent manner. The current drug therapy of choice is to timely resupply the blood to the ischemic tissue; but reperfusion may introduce additional harm to the tissue through a process known as ischemia/reperfusion injury. As such, new drugs that would complement reperfusion by providing neural and cardiovascular protection and by targeting multiple abnormalities in ischemia are receiving increased attention. Scutellarin is an herbal flavonoid glucuronide with multiple pharmacological activities. Owing to its multiple beneficial effects, such as anti-oxidant, anti-inflammation, vascular relaxation, anti-platelet, anti-coagulation, and myocardial protection, scutellarin has been used clinically to treat stroke, myocardial infarction, and diabetic complications. Over the past three decades, clinical and pharmacological studies have accumulated a body of evidence that not only demonstrated these therapeutic effects, but also provided significant insights into the pharmacokinetic behavior, therapeutic profile, and mode of action of scutellarin in humans and animal models. Medicinal modification and new drug delivery methods have led to the development of new derivatives and formulations of scutellarin with improved bioavailability, efficacy, and safety. Here we review the current literature on scutellarin to provide a comprehensive understanding of the pharmacological activity, mechanism of action, toxicity, and therapeutic potential of scutellarin for the treatment of ischemia, diabetic complications, and other chronic diseases.

Energy Drinks and Their Impact on the Cardiovascular System: Potential Mechanisms.

Globally, the popularity of energy drinks is steadily increasing. Scientific interest in their effects on cardiovascular and cerebrovascular systems in humans is also expanding and with it comes a growing number of case reports of adverse events associated with energy drinks. The vast majority of studies carried out in the general population report effects on blood pressure and heart rate. However, inconsistencies in the current literature render it difficult to draw firm conclusions with regard to the effects of energy drinks on cardiovascular and cerebrovascular variables. These inconsistencies are due, in part, to differences in methodologies, volume of drink ingested, and duration of postconsumption measurements, as well as subject variables during the test. Recent well-controlled, randomized crossover studies that used continuous beat-to-beat measurements provide evidence that cardiovascular responses to the ingestion of energy drinks are best explained by the actions of caffeine and sugar, with little influence from other ingredients. However, a role for other active constituents, such as taurine and glucuronolactone, cannot be ruled out. This article reviews the potentially adverse hemodynamic effects of energy drinks, particularly on blood pressure and heart rate, and discusses the mechanisms by which their active ingredients may interact to adversely affect the cardiovascular system. Research areas and gaps in the literature are discussed with particular reference to the use of energy drinks among high-risk individuals.

[Abuse of energy drinks: does it pose a risk?]. / L'abus de boissons énergisantes présente-t-il un risque ?

BACKGROUND: Energy drinks designate "any product in the form of a drink or concentrated liquid containing a mixture of ingredients having the property to raise the level of energy and liveliness". Their introduction has raised many reluctance and reserves after numerous cardiovascular and neurological injuries among regular consumers. OBJECTIVE: This article attempts to synthesize the existing literature on energy drinks. The review focuses to show that excessive energy drinks consumption cause many complications. METHODS: The literature review was conducted from 2001 to 2014, using PubMed, Google Scholar, EMBASE, and PsycInfo, using the following keywords alone or combined: energy drinks, caffeine, taurine, toxicity, dependence, complications. RESULTS: Occasional or moderate consumption of these cans seem to present little risk to healthy adults. However, their repeated consumption in proportions that far exceed the recommendations for recommended use by the manufacturers, combined with the use of alcohol or illicit drugs consumption increases the risk of occurrence of somatic and psychiatric complications, especially among underage, and subjects with cardiovascular and neurological history. CONCLUSION: Repeated consumption of energy drinks increases the risk of somatic and psychiatric complications. Further studies must be controlled to improve our understanding of other possible negative consequences on health.

Incidence of hydromorphone-induced neuroexcitation in hospice patients.

BACKGROUND AND OBJECTIVE: To date, there are no known published studies that prospectively followed hospice patients receiving hydromorphone to evaluate the development of hydromorphone-induced neuroexcitation (HINE). The first objective of this study was to determine the incidence of HINE. The second objective was to identify factors influencing the presence or absence of HINE symptoms in hospice patients. METHODS: This was a noninterventional, prospective study. This study population included hospice patients 18 years of age or older who were admitted to one of two Nathan Adelson Hospice inpatient units in Las Vegas, Nevada, and were initiated on a scheduled regimen of hydromorphone. A total of 156 patients were enrolled and analyzed in this study. Data collection was performed by the study investigators using a standard data tracking form, including hospice diagnosis, gender, renal function, hydromorphone regimen, and whether or not the patient experienced neuroexcitatory symptoms. Data collection occurred from November 2010 to March 2011. RESULTS AND CONCLUSIONS: Based on the data collected in this study, it appears that the likelihood of HINE does increase with larger doses, increasing age, increasing serum creatinine, and the presence of malignant neoplasm. However, after adjusting for the variables in the logistic regression model, diagnosis of malignant neoplasm was not a significant predictor of HINE. Future studies may focus on evaluating metabolite levels, such as hydromorphone-3-glucuronide (H3G), in patients developing HINE symptoms. This may help to determine if the metabolites of opioids, such as H3G, are involved in the development of the neurotoxic symptoms.

Selective fraction of Scutellaria baicalensis and its chemopreventive effects on MCF-7 human breast cancer cells.

Based on our previous observation, the whole Scutellaria baicalensis extract (SbE) did not show significant breast cancer cell inhibitory effect. In this study, we isolated a baicalin-deprived-fraction (SbF1) of Scutellaria baicalensis, and baicalin-fraction (SbF3), and evaluated their anti-breast cancer properties using MCF-7 cells. The content of four flavonoids in extract/fractions were determined using high performance liquid chromatography. Analytical data showed that in SbF1, the major constituents are baicalein and wogonin, while SbF3 only contains baicalin. The antiproliferative effects of fractions and SbE were assayed using modified trichrome stain method. SbF1 showed significant antiproliferative effect. Treated with 100mug/ml of SbF1 for 72h inhibited MCF-7 cell growth by 81.6%, while in the same treatment concentration, SbF3 increased cell growth by 22.6%. SbF1 was recognized as an active fraction of SbE. The effects of four flavonoids in SbE, scutellarin, baicalin, baicalein and wogonin, were determined, and data showed that baicalein and wogonin significantly inhibited MCF-7 cell growth. In contrast, in certain concentrations, scutellarin and baicalin increased cancer cell growth. The effects of SbF1 on cell cycle and apoptosis were assayed using flow cytometry. SbF1 arrested MCF-7 cells in S- and G2/M-phases, and significantly increased induction of cell apoptosis. These combined phytochemical and biological data provide evidence for further chemopreventive studies of the baicalin-deprived SbE on breast cancer.

Protective effects of scutellarin and breviscapine on brain and heart ischemia in rats.

Scutellarin is an active molecule existing in Erigeron breviscapus (vant.) Hand-Mazz. The present work was designed to study the antiischemic effects of scutellarin and its mixture with another substance, breviscapine, in male Sprague-Dawley (SD) rats. Ligature of left anterior descending arteries was performed to induce acute myocardial infarction (MI), and the middle cerebral artery occlusion was created to induce focal cerebral ischemia. The MI size was significantly reduced by scutellarin (15 and 50 mg/kg) but not by breviscapine (5 to 50 mg/kg); the effect of scutellarin on the anti-MI was dose-dependent. Compared with control group, scutellarin (50 mg/kg) reduced the myocardium cell apoptosis in MI rats. The two drugs together (5 to 50 mg/kg) significantly reduced infarction size in focal brain ischemic rats (P < 0.05). There were no significant differences among the 3 dosages in breviscapine-treated rats, and the effect of scutellarin on the anticerebral ischemia was dose-dependent. The results demonstrate that the protective effects of scutellarin on cardiovascular and cerebrovascular ischemia were better than its mixture, breviscapine, in rats.

Adverse events caused by drug interactions involving glucuronoconjugates of zidovudine, valproic acid and lamotrigine, and analysis of how such potential events are discussed in package inserts of Japan, UK and USA.

BACKGROUND AND OBJECTIVE: As pharmacokinetic drug interactions frequently cause adverse events, it is important that the relevant information is given in package inserts (PIs). We previously analysed the provision of PIs for HMG-CoA reductase inhibitors and Ca antagonists, for which metabolism by cytochrome P450 could be a major interaction mechanism. In this article, we focus on interactions involving glucuronoconjugates because many drugs and their metabolites undergo this conjugation. METHODS: We reviewed clinical drug interactions related to glucuronoconjugates, focusing on reports of adverse events. Then, we picked out three important drugs (zidovudine, valproic acid and lamotrigine), and examined how the literature information is reflected in the relevant PIs in Japan, UK and USA. RESULTS AND DISCUSSION: Pharmacokinetic interactions related to glucuronoconjugates were found with 33 drug combinations. Of these, five combinations induced clear adverse events: (i) severe anaemia due to zidovudine and caused by interaction with valproic acid, (ii) recurrence/increased frequency of seizure or increased manic states from a reduction in therapeutic effects of valproic acid caused by panipenem, (iii) meropenem or (iv) ritonavir and (v) of lamotrigine caused by oral contraceptives. Analysis of PIs showed a lack of description of the interaction of zidovudine with valproic acid in the Japanese PI. The UK PI mentioned this interaction without quantitative data, whereas full information was given in the US PI. A lack of description was also present on the interaction between valproic acid with ritonavir, reported in 2006, in the PIs of all three countries. For the interactions involving valproic acid and panipenem or meropenem, even though marked reduction of blood valproic acid level has been reported, no quantitative data were provided in any of the PIs. CONCLUSION: Five combinations were identified to cause severe adverse events because of interactions related to glucuronoconjugates. This information, including quantitative data, is not always properly provided in the relevant PIs in Japan, UK or USA. PIs should be improved to better inform healthcare providers and thereby help them and their patients.

Inhibition of mammary tumor growth by a novel nontoxic retinoid: chemotherapeutic evaluation of a C-linked analog of 4-HPR-glucuronide.

Previous studies from our laboratory suggest that 4-HPROG, the O-glucuronide derivative of 4-HPR, has improved mammary cancer chemopreventive/ antitumor activities as well as reduced toxicity, as compared to 4-HPR. This O-linked glucuronide derivative is a substrate to the P-glucuronidase enzyme and may also undergo hydrolysis in vivo to the vitamin A metabolite, retinoic acid, that is toxic at high concentrations. In an effort to improve analog potency relative to its toxicity, the 4-HPROG's phenolic oxygen was replaced with a methylene group, thus preventing biological cleavage of the glucuronide moiety. The resulting C-linked analog, 4-HPR-C-glucuronide (4-HPRCG), cannot be hydrolyzed to 4-HPR. The results of this study show that 4-HPRCG is an effective chemotherapeutic agent that caused 49% regression of DMBA-induced mammary tumors in rats, while showing almost no side-effects that are often observed with other natural or synthetic retinoids, such as a reduction in blood retinol level, elevation in blood triglyceride (TG) level, and decrease in bone mineral content (BMC). These results suggest that 4-HPRCG should be considered as a better candidate for breast cancer treatment.

Mycophenolic acid pharmacokinetics and related outcomes early after renal transplant.

AIMS: The pharmacokinetics of mycophenolic acid and its glucuronide are complex. This study investigated the pharmacokinetics, pharmacodynamics and protein binding of mycophenolic acid and its glucuronide metabolite, early post-transplant in renal allograft recipients. METHODS: Forty-two de novo renal transplant recipients receiving mycophenolate mofetil and concomitant cyclosporin (n = 32) or tacrolimus (n = 10) participated in the study. Blood samples were taken on day 5 post-transplant for measurement of free and total concentrations of mycophenolic acid, mycophenolic acid glucuronide and relevant biochemistry. Associations between free fraction and biochemistry were investigated. Free and total 6-h area under the concentration-time curve (AUC0-6) of mycophenolic acid was assessed relative to clinical outcomes in the first month post-transplant. RESULTS: Kinetic variability of free and total mycophenolic acid and its glucuronide was greater in patients on cyclosporin (12- to 18-fold variation) than on tacrolimus (four- to fivefold) cotherapy. Cyclosporin-treated patients also had significantly lower predose total mycophenolic acid concentrations than tacrolimus-treated patients (median 0.8 mg l(-1) and 1.6 mg l(-1), respectively, P = 0.002). Mycophenolic acid glucuronide predose concentration correlated positively with mycophenolic acid glucuronide AUC0-6 (r > 0.95). Mycophenolic acid free fraction varied 11-fold, from 1.6% to 18.3%, whilst the glucuronide free fraction varied threefold, from 17.4% to 54.1%. Urea and creatinine concentrations correlated positively (r > 0.46), whilst albumin correlated negatively (r = -0.54) with free fraction of mycophenolic acid. Similar relationships were found for the free fraction of mycophenolic acid glucuronide. Mycophenolic acid free fraction was on average 70% higher in patients with albumin concentrations below a specified albumin cut-off concentration of 31 g l(-1)[free fraction = 7 +/- 4% for lower albumin and 4 +/- 3% for higher albumin, respectively; P = 0.001; 95% confidence interval (CI) for the difference 1.9, 4.2]. Neither free nor total mycophenolic acid AUC0-6 was related to rejection (P > 0.07). Free AUC0-6 was significantly higher in those patients with thrombocytopenic, leukopenic and/or infectious outcomes than in those without (mean +/- SD 1.9 +/- 0.3 mg h(-1) l(-1) and 1.1 +/- 0.1 mg h(-1) l(-1), P = 0.0043; 95% CI for the difference 0.3, 1.4). CONCLUSIONS: The marked variability in mycophenolic acid/glucuronide pharmacokinetics occurring early post-transplant during the current study was greater in cyclosporin (12-18-fold) than in tacrolimus (four- to fivefold) treated patients. Concomitant cyclosporin was associated with total mycophenolic acid concentrations approximately half that of tacrolimus. Patients with marked renal impairment had the highest free fractions reported to date. The exposure to unbound mycophenolic acid was significantly related to infections and haematological toxicity.

Clinical pharmacokinetics of irinotecan and its metabolites in relation with diarrhea.

OBJECTIVES: Our objective was to build population pharmacokinetic models that describe plasma concentrations of irinotecan (CPT-11) and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38) and SN-38 glucuronide (SN-38G) and to investigate the pharmacokinetic-pharmacodynamic relationships between drug exposure and diarrhea, the major dose-limiting toxicity. METHODS: Data were obtained from 109 patients (65 men and 44 women) who received 1.5-hour (range, 0.75- to 2.25-hour) intravenous infusions of irinotecan at doses that ranged from 100 to 350 mg/m(2); 44 patients had a second course. The population pharmacokinetic models were developed to describe plasma concentration-time profiles. The area under the concentration-time curve from time zero to 60 hours [AUC (0-60)] was used as a measure of drug exposure to model the probabilities of diarrhea with use of a logistic regression model. RESULTS: A 3-compartment pharmacokinetic model best described the disposition of irinotecan, whereas SN-38 and SN-38G showed 2-compartmental characteristics. The population estimate of clearance for irinotecan was 31.6 L/h, and the volume of distribution at steady-state (V(SS)) was 263 L. The clearance divided by formation fraction (F(m)) was 712 L/h and 66.8 L/h for SN-38 and SN-38G, respectively. The V(SS)/F(m) was 72,000 L for SN-38 and 85.4 L for SN-38G. The frequencies of diarrhea scores in this study were 46% (grade 0), 28% (grade 1), 20% (grade 2), 4% (grade 3), and 2% (grade 4). Significant correlations between AUC(0-60) and diarrhea scores were found for irinotecan (P <.05) and SN-38G (P <.01) but not for SN-38 or the biliary index. CONCLUSIONS: In this population analysis, irinotecan and SN-38G AUC values were appropriate predictors of the risk for diarrhea, and SN-38G AUC showed the stronger relationship of the two. The developed population models may be useful in further clinical development of this agent.

Efficacy and safety of oral betaine glucuronate in non-alcoholic steatohepatitis. A double-blind, randomized, parallel-group, placebo-controlled prospective clinical study.

In a prospective, randomized, double-blind therapeutic trial, 191 patients with non-alcoholic steatohepatitis were treated for 8 weeks daily b.i.d. orally either with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate (Ietepar) (96 patients) or with undistinguishable placebo capsules (95 patients). The verum treatment effectively reduced by 25% hepatic steatosis (p < 0.01) and by 6% hepatomegaly (p < 0.05), while placebo did not significantly reduce the disorders. Verum was also more effective than placebo on discomfort in abdominal upper right quadrant. The global efficacy of treatment was rated by the doctor "very good" or "good" in 48% of verum treated patients and only in 17% after placcbo (P of difference = 9 x 10(-6)). 52% of patients self-rated efficacy as "very good" or "good" after verum and only 34% after placebo (P of difference = 0.017). The verum treatment provoked a significant reduction of the increased liver transaminases (ALT, AST and gamma-GT) while placebo was ineffective. Adverse events were recorded in 10% of verum-treated patients and in 7% under placebo (no significant difference). In both groups the adverse events were mild and transient, did not require treatment discontinuation and were undistinguishable from common symptoms of liver disorders. In conclusion, the 8-week treatment with betaine glucuronate combined with diethanolamine glucuronate and nicotinamide ascorbate was found effective in non-alcoholic steatohepatitis, a disorder for which the hitherto pharmacological interventions were poorly and inconsistently effective.

Flavopiridol metabolism in cancer patients is associated with the occurrence of diarrhea.

Flavopiridol, a cyclin-dependent kinase inhibitor currently undergoing clinical evaluation, has a dose-limiting toxicity of diarrhea. Preclinical data on flavopiridol metabolism indicate that flavopiridol undergoes hepatic glucuronidation. The purpose of this study is to evaluate whether the occurrence of diarrhea is related to the systemic glucuronidation of flavopiridol. Parent drug and metabolite concentrations in plasma were measured by high-pressure liquid chromatography in 22 metastatic renal cancer patients treated on a Phase II trial of 50 mg/m2/day of flavopiridol administered every 2 weeks as a 72-h continuous infusion. Pharmacokinetics of flavopiridol and its glucuronide were assessed during the first cycle at 23, 47, and 71 h during the infusion. Flavopiridol concentrations at 23, 47, and 71 h were 389 nM (296-567 nM), 412 nM (297-566 nM), and 397 nM (303-597 nM) [median (interquartile range)], respectively. Flavopiridol glucuronide reached a plateau of 358 nM (196-553 nM) at 47 h. Metabolic ratios of flavopiridol glucuronide:flavopiridol at 71 h showed an apparent bimodal distribution with an antimode of 1.2. Thirteen patients experienced diarrhea and had lower metabolic ratios [0.72 (0.53-0.86)] than patients without diarrhea [2.24 (1.76-2.3); P = 0.002]. Eight of 11 extensive glucuronidators (ratio > 1.2) did not develop diarrhea, whereas 10 of 11 poor glucuronidators (ratio < 1.2) developed diarrhea (P = 0.008). The glucuronidation of flavopiridol is apparently polymorphic, suggesting a genetic etiology. The systemic glucuronidation of flavopiridol is inversely associated with the risk of developing diarrhea.

Immune hemolytic anemia caused by sensitivity to a metabolite of etodolac, a nonsteroidal anti-inflammatory drug.

BACKGROUND: Immune hemolytic anemia can be caused by sensitivity to many different drugs. In some instances, the sensitizing compound can be identified by in vitro testing, but results are often negative. One reason for this is that a drug metabolite formed in vivo can be the sensitizing agent, but the responsible metabolites have rarely been identified at a chemical level. This report describes a patient who developed severe, Coombs-positive hemolytic anemia on two occasions after taking the nonsteroidal anti-inflammatory drug etodolac. Studies were performed to characterize etodolac metabolites to which this patient was sensitive. CASE REPORT: Serum was tested for antibody in the presence and absence of drug using conventional methods and urine from individuals taking etodolac as a source of drug metabolites. Urinary metabolites of etodolac were identified by high-pressure liquid chromatography analysis. Glucuronide conjugates of etodolac and the 6-OH metabolite of etodolac were synthesized in a rat liver microsomal system to obtain reference standards. RESULTS: The patient's serum gave only trace (+/-) reactions with normal RBCs in the presence of etodolac but reacted strongly (4+) in the presence of urine from an individual taking this drug. The active urinary metabolites were identified as etodolac glucuronide and 6-OH etodolac glucuronide. CONCLUSION: This patient appears to have experienced acute, severe immune hemolytic anemia on two occasions because of sensitivity to the glucuronides of etodolac and 6-OH etodolac. In patients suspected of having drug-induced immune hemolytic anemia, RBC-reactive antibodies can sometimes be detected by using urine from an individual taking the implicated medication as the source of drug metabolites in in vitro reactions. For patients who present with acute immune hemolysis, a careful history of drug exposure should be taken, and, where indicated, confirmatory testing should be performed to identify the sensitizing drug and prevent inadvertent reinduction of hemolysis at a later time.

[Delusion and sleep deprivation]. / Bouffée délirante et privation de sommeil.

In this article, the authors report two observations of short delusion that occurred after taking Guronsan--a psychostimulant commercialized in France--for a few days, with the intention of maintaining a total deprivation of sleep for three days in both cases. The ensuing clinical picture included a state of depersonalization, a loss of the sense of reality, illusions and even visual hallucinations as well as a delirious feeling of persecution. These disorders altered with the state of vigilance and the patients remembered them clearly. The authors discussed the etiopathogenic role of this psychotrope, as its components--acid ascorbic, glucuronamide and caffein--are not mentioned in literature as causing factors of a psychotic state. Then they compared this psychotrope with other molecules: amphetamines in particular may start a delirium of persecution, but normally they just reveal an underlying psychotic structure, which doesn't seem to be the case here, where the two young adults were only found a little immature. Chloroquine has sometimes been incriminated for disorders similar to those mentioned above, with a difference lying in a greater stability in the duration of these disorders that would persist several days after the end of the treatment. The clinical picture of the two cases was more labile and sedation was complete as soon as the absorption of the psychotrope was interrupted and sleep was restored at the same time. That is why the authors emphasize the importance of the deprivation of sleep as a causing factor of those delusion disorders which have particularly been observed in the case of solitary navigators. The psychiatrist dealing with emergencies shouldn't overlook this clinical and etiological possibility, all the less so as the treatment is simple and the resort to neuroleptics unnecessary.