Toxicodynetics in nordiazepam and oxazepam overdoses.

OBJECTIVES: Toxicodynetics aims at defining the time-course of major clinical events in drug overdose. We report the toxicodynetics in mono-intoxications with oxazepam and nordiazepam. METHODS: Cases of oxazepam or nordiazepam overdoses collected at the Paris poison control centre from 1999 to 2014 on the basis of self-report. A particular attention was paid to eliminate the concomitant alcohol or psychotropic co-ingestions. The toxicodynetic parameters were assessed as previously described. Results are expressed using 10-90 percentiles. In adults, the dose was normalized (TI, toxic Index) by dividing the supposed ingested dose by the maximal recommended dose. RESULTS: Two hundred and fifty-one and 74 cases of oxazepam and nordiazepam poisonings were included, respectively. The Emax for oxazepam and nordiazepam were sleepiness or obtundation in 106 and 36 cases, respectively. Coma was used to qualify only one oxazepam overdose. The median delay in onset of the Emax was 1.5h (0.33-15) in nordiazepam and 4h (0.5-15) in oxazepam overdose. In both overdoses, the onset of Emax occurred on an "on-off" mode. In adults, the greatest TIs in nordiazepam and oxazepam overdoses were 45 and 26.7, respectively. The TI in the oxazepam-induced coma was 26.7, the largest dose. CONCLUSION: Data collected in PCC allow determining a number of toxicodynetic parameters. Toxicodynetics showed that nordiazepam is not a cause of coma even in large overdose while oxazepam causes coma only at a very high dose. Deep coma in nordiazepam overdose whatever the dose and deep coma in overdose with oxazepam involving TI less than 20 result from unrecognized drug-drug interaction.

Safety and Abuse Liability of Oxazepam: Is This Benzodiazepine Drug Underutilized?

Benzodiazepine drugs are controversial because of safety and abuse liability concerns, although they have clinically relevant pharmacological differences. The current article reviews studies pertaining to the pharmacology, safety, and abuse liability of oxazepam. Compared to other benzodiazepine drugs, oxazepam has a favorable safety and abuse liability profile, which may be related to its pharmacology. Oxazepam is more slowly absorbed and enters the brain more slowly than other benzodiazepine drugs; it does not have active metabolites and does not accumulate with chronic dosing; its metabolism is not affected by age or by mild/moderate liver disease; and it is not prone to drug-drug interactions. Oxazepam also binds to the translocator protein, which stimulates the synthesis of neurosteroids, and this effect may contribute to its reduced abuse liability.

Mixed myoclonic-absence status epilepticus in juvenile myoclonic epilepsy.

Myoclonic status epilepticus or mixed absence-myoclonic status is uncommon in juvenile myoclonic epilepsy (JME), often precipitated by sleep deprivation, withdrawal of medication, or inadequate antiepileptic drugs (Thomas et al., 2006; Crespel et al., 2013). Such episodes respond well to benzodiazepines or valproate (Crespel et al., 2013). We present the video-EEG of a 24-year-old woman with JME and bipolar disorder. She had a confusional state five days after withdrawal of clonazepam (14 mg/d) and introduction of oxazepam (200 mg/d), followed by catatonic stupor with subtle myoclonus of the face and the arms. The EEG showed absence status (figures 1, 2), which stopped after IV injection of clonazepam (1 mg) (figure 3). Consciousness returned to normal [Published with video sequence and figures (1)].

Influence of central nervous system-acting drugs on results of cognitive testing in geriatric inpatients.

INTRODUCTION: Growing evidence shows a high correlation between extensive use of central nervous system-acting drugs (CNSADs) in elderly patients and adverse drug reactions (ADRs) such as falls, fractures, and mortality. RESEARCH QUESTION: Are results of cognitive testing with the Mini Mental Status Examination (MMSE) influenced by use of CNSADs? SETTING: Geriatric inpatient service for acute, subacute, and rehabilitation care. METHODS: Secondary combined analysis of two prospective, single-center study cohorts (PROPSYC, 2011 and AGE OUT, 2012) with identical procedure for the MMSE at a tertiary hospital. RESULTS: Overall, 395 patients were included, 144 male (M) and 251 female (F). Mean age was 80.0 ± 8.4 years (M 76.7 ± 9.1, F 81.9 ± 7.3, p = 0.0000). Mean MMSE points were 22.9 ± 4.8 (M 23.2 ± 4.6, F 22.6 ± 5.0, p = 0.211). In total, 258 patients (65.3 %) used drugs with potential adverse cognitive properties. Analgesics with central activity were given to 117 of 395 patients (29.6 %). Low-potency opioids (tramadol hydrochloride, tilidine) were identified in 60 patients and high-potency opioids in 57 patients. Antidepressants were used in 66 patients, benzodiazepines in 26, and hypnotics in 11, while 38 patients received other CNSADs. We only found significant correlations with the results of cognitive testing for sedatives (diazepam and oxazepam, Pearson's r - 0.79, p = 0.05), but not for lorazepam. CONCLUSION: Our analysis shows an influence of sedatives (diazepam and oxazepam, but not lorazepam) on cognitive testing with the MMSE in users of CNSADs.

Oxazepam Detected in Urine 79 Days After Withdrawal of Diazepam: A Case Report.

ABSTRACT: Patients suffering from substance use disorder, including for instance benzodiazepines, may have comorbidity with attention deficit hyperactivity disorder (ADHD). Centrally acting stimulants play an important role in the treatment of ADHD. Before such treatment can be initiated, withdrawal of benzodiazepines may be necessary. Urine testing is the preferred method for monitoring adherence in benzodiazepine withdrawal, but there is a lack of studies reporting detection time. Here, we report a case of a 30-year-old woman with substance use disorder and ADHD who had detectable metabolites of diazepam 79 days after withdrawal. To our knowledge, no cases with detection time equivalent to this have previously been published. This case report serves as an example that clinicians may need to consider interindividual pharmacokinetic characteristics when interpreting the results of urine drug tests, and that a positive urine test may still be consistent with abstinence from a certain drug. In the current case, a high body mass index and a genetic polymorphism gave a reasonable explanation for the prolonged detection of diazepam metabolites.

Duloxetine-related panic attacks.

Side-effects arising on the grounds of antidepressant administration pose as a substantial obstacle hindering successful depressive disorder treatment. Side-effects, especially those severe or those manifested through dramatic clinical presentations such as panic attacks, make the treatment far more difficult and shake patients' trust in both the treatment and the treating physician. This case report deals with a patient experiencing a moderately severe depressive episode, who responded to duloxetine treatment administered in the initial dose of 30 mg per day with as many as three panic attacks in two days. Upon duloxetine withdrawal, these panic attacks ceased as well. The patient continued tianeptine and alprazolam treatment during which no significant side-effects had been seen, so that she gradually recovered. Some of the available literature sources have suggested the possibility of duloxetine administration to the end of generalised anxiety disorder and panic attack treatment. However, they are outnumbered by the contributions reporting about duloxetine-related anxiety, aggressiveness and panic attacks. In line with the foregoing, further monitoring of each and every duloxetine-administered patient group needs to be pursued so as to be able to evaluate treatment benefits and weigh them against risks of anxiety or panic attack onset.

Reinforcement of irritability during therapy with benzodiazepines.

BACKGROUND: Often, long-term treatment with benzodiazepines is a subject of discussion due to potential side effects, with dependence on benzodiazepines as the most serous one. After longer period of benzodiazepines tolerance on their anxiolytic effects develops. Discontinuation is usually beneficial as it is followed by improved psychomotor and cognitive functioning, particularly in the elderly. Previous studies confirmed occurrence of physical dependence in high percentage of patients in long term treatment with benzodiazepines at therapeutic dosages. Benzodiazepines are relatively well-tolerated medicines but can induce serious problems of addiction and that is why their use is regulated. The aim of this article is to report a case of a patient who was taking 15 tablets of oxazepam daily for a period of time, during which reinforcement of irritability occurred. CONCLUSION: It is necessary to warn patients who take benzodiazepines in therapy that reinforcement of irritability may occur in case of higher dosage of benzodiazepines, which may be misinterpreted as worsening in mental condition.

Oxazepam and cognitive reappraisal: A randomised experiment.

BACKGROUND: Cognitive reappraisal is a strategy for emotional regulation, important in the context of anxiety disorders. It is not known whether anxiolytic effects of benzodiazepines affect cognitive reappraisal. AIMS: We aimed to investigate the effect of 25 mg oxazepam on cognitive reappraisal. METHODS: In a preliminary investigation, 33 healthy male volunteers were randomised to oxazepam or placebo, and then underwent an experiment where they were asked to use cognitive reappraisal to upregulate or downregulate their emotional response to images with negative or neutral emotional valence. We recorded unpleasantness ratings, skin conductance, superciliary corrugator muscle activity, and heart rate. Participants completed rating scales measuring empathy (Interpersonal Reactivity Index, IRI), anxiety (State-Trait Anxiety Inventory, STAI), alexithymia (Toronto Alexithymia Scale-20, TAS-20), and psychopathy (Psychopathy Personality Inventory-Revised, PPI-R). RESULTS: Upregulation to negative-valence images in the cognitive reappraisal task caused increased unpleasantness ratings, corrugator activity, and heart rate compared to downregulation. Upregulation to both negative- and neutral-valence images caused increased skin conductance responses. Oxazepam caused lower unpleasantness ratings to negative-valence stimuli, but did not interact with reappraisal instruction on any outcome. Self-rated trait empathy was associated with stronger responses to negative-valence stimuli, whereas self-rated psychopathic traits were associated with weaker responses to negative-valence stimuli. CONCLUSIONS: While 25 mg oxazepam caused lower unpleasantness ratings in response to negative-valence images, we did not observe an effect of 25 mg oxazepam on cognitive reappraisal.

Behavioural effects of psychoactive pharmaceutical exposure on European perch (Perca fluviatilis) in a multi-stressor environment.

With the ability to resist biodegradation and exert therapeutic effects at low concentrations, pharmaceutical contaminants have become environmental stressors for wildlife. One such contaminant is the anxiolytic oxazepam, a psychoactive pharmaceutical that is frequently detected in surface waters globally. Despite growing interest in understanding how wildlife respond to anxiolytics, synergistic effects of pharmaceuticals and other abiotic (e.g. temperature) and biotic (e.g. predation risk) stressors remain unclear. Here, using a multi-stressor approach, we investigated effects of 7-day oxazepam exposure (6.5 µg/L) on anxiety-related behaviours in juvenile European perch (Perca fluviatilis). The multi-stressor approach was achieved by exposing perch to oxazepam at two temperatures (10 °C and 18 °C), and at two predation risk regimes-generated using chemical cues from the northern pike (Esox lucius). Our exposures resulted in a successful uptake of the drug from the water, i.e., oxazepam was measured in perch muscle tissue at 50 ±â€¯17 ng/g (mean ±â€¯SD). We found significant oxazepam-induced effects on boldness, with 76.7% of the treated fish entering the white background (i.e. 'exposed' area where exposure to presumed risks are higher) within the first 5 min, compared to 66.6% of the control fish. We also found a significant effect of temperature on total time spent freezing (i.e. staying motionless). Specifically, fish in the low temperature treatments (oxazepam, predation) froze for longer than fish in high temperatures. Our multi-stressor study is the first to uncover how anxiety-related behaviours in wild juvenile fish are altered by changes in water temperature and perceived predation risk. Importantly, our findings highlight the need to focus on multiple stressors to improve understanding of how organisms not only survive, but adapt to, human-induced environmental change.

Behavioural alterations induced by the anxiolytic pollutant oxazepam are reversible after depuration in a freshwater fish.

Anthropogenic pharmaceutical pollutants have been detected in nature across the globe, and recent work has shown negative effects of pharmaceuticals on the health and welfare of many animals. However, whether alterations can be reversed has been poorly investigated, although such studies are essential to assess the effects of high-peak exposure events in waterways where pharmaceutical concentrations are usually low. In this study, we investigated the effects of two concentrations (environmentally relevant 1 µg L-1 and high 100 µg L-1) of oxazepam, an anxiolytic commonly detected in aquatic environments, and whether behavioural alterations are reversible after depuration. Specifically, we measured daytime and night-time swimming activity and daytime behaviours related to boldness (foraging, sheltering and routine swimming activity) using the freshwater burbot (Lota lota). We found that both swimming activity and boldness were affected by oxazepam. Fish exposed to the higher level had a higher burst swimming duration (i.e., fast swimming bouts), both in the daytime and night-time trials. Further, fish exposed to the lower oxazepam level spent less time sheltering than control- and high-level exposed fish, but there was no difference between the control and high oxazepam treatments. For routine swimming activity, quantified in the boldness trials, and for latency to forage, there were no treatment effects. When retesting the fish after depuration, the detected behavioural alterations were no longer present. Since the magnitude of these effects were not consistent across endpoints, our study suggests that oxazepam might not be a great concern for this particular, stress tolerant, species, highlighting the importance of evaluating species-specific effects of pharmaceuticals. The observation that the effects we did find were reversible after depuration is encouraging, and indicates that rapid restoration of behaviours after removal from oxazepam contamination is possible.

An observational study of benzodiazepine prescription during inpatient alcohol detoxification for patients with vs. without chronic pretreatment with high-dosage baclofen.

High-dose baclofen is prescribed as a maintenance treatment to reduce alcohol use in patients with alcohol use disorder. Nevertheless, some patients still have massive alcohol intakes and require inpatient alcohol withdrawal. To compare the oral dose of benzodiazepine prescribed to manage alcohol withdrawal symptoms in patients with vs. without steady-state pretreatment with high-dose baclofen. Retrospective chart review study. Prescribed benzodiazepine dose expressed in diazepam-equivalent was compared between groups. Thirty-one patients were assessed in the high-dose maintenance baclofen group and compared to 31 matched patients not receiving baclofen. No statistically significant difference was evident between groups regarding levels of benzodiazepines prescribed. The mean diazepam-equivalent dose during the first 7 days was 294 ± 149 mg in the baclofen group vs. 310 ± 133 mg (t-test = 0.440, P = 0.661) in matched controls. Steady-state high-dose baclofen before an inpatient alcohol cessation hospitalization does not lower the needed benzodiazepine dose in the management of alcohol withdrawal symptoms.

Associations between use of benzodiazepines or related drugs and health, physical abilities and cognitive function: a non-randomised clinical study in the elderly.

OBJECTIVE: To describe associations between the use of benzodiazepines or related drugs (BZDs/RDs) and health, functional abilities and cognitive function in the elderly. METHODS: A non-randomised clinical study of patients aged > or =65 years admitted to acute hospital wards during 1 month. 164 patients (mean age +/- standard deviation [SD] 81.6 +/- 6.8 years) were admitted. Of these, nearly half (n = 78) had used BZDs/RDs before admission, and the remainder (n = 86) were non-users. Cognitive ability was assessed by the Mini-Mental State Examination (MMSE). Patients scoring > or =20 MMSE sum points were interviewed (n = 79) and questioned regarding symptoms and functional abilities during the week prior to admission. Data on use of BZDs/RDs before admission, current medications and discharge diagnoses were collected from medical records. Health, physical abilities and cognitive function were compared between BZD/RD users and non-users, and adjustments were made for confounding variables. The residual serum concentrations of oxazepam, temazepam and zopiclone were analysed. RESULTS: The mean +/- SD duration of BZD/RD use was 7 +/- 7 years (range 1-31). Two or three BZDs/RDs were concomitantly taken by 26% of users (n = 20). Long-term use of these drugs was associated with female sex and use of a higher number of drugs with effects on the CNS, which tended to be related to diagnosed dementia. After adjustment for these variables as confounders, use of BZDs/RDs was not associated with cognitive function as measured by the MMSE. However, use of BZDs/RDs was associated with dizziness, inability to sleep after awaking at night and tiredness in the mornings during the week prior to admission and with stronger depressive symptoms measured at the beginning of the hospital stay. Use of BZDs/RDs tended to be associated with a reduced ability to walk and shorter night-time sleep during the week prior to admission. A higher residual serum concentration of temazepam correlated with a lower MMSE sum score after adjustment for confounding variables. CONCLUSIONS: Long-term use and concomitant use of more than one BZD/RD were common in elderly patients hospitalised because of acute illnesses. Long-term use was associated with daytime and night-time symptoms indicative of poorer health and potentially caused by the adverse effects of these drugs.

Methylphenidate-induced information processing dysfunction in nonschizophrenic patients.

To examine the relationship of aminergic overactivity to information processing, we gave methylphenidate hydrochloride, oxazepam, or placebo to 12 nonpsychotic patients in one-week blocks in a double-blind, randomized design. Methylphenidate induced a pattern of information processing dysfunction similar to that seen in schizophrenic patients, strengthening the linkage of the schizophrenia-information processing dysfunction-aminergic overactivity relationship. Further, the time course of the observed deficits in both schizophrenic and methylphenidate-induced states is strikingly compatible with the temporal mapping pattern of monoaminergic neuronal systems. More research is needed to identify definitively the aminergic influences on attentional functioning. A psychophysical task-pharmacologic probe strategy should prove useful.

An unusual case of diarrhoea.

Case histories are based on actual medical negligence claims, however certain facts have been omitted or changed by the author to ensure the anonymity of the parties involved. Medication errors in general practice are relatively common. This article describes a medication error that led to a patient complaint and claim.

Is long-term use of benzodiazepine a risk for cancer?

The carcinogenicity of benzodiazepines (BZDs) is still unclear. We aimed to assess whether long-term benzodiazepines use is risk for cancer.We conducted a longitudinal population-based case-control study by using 12 years from Taiwan National Health Insurance database and investigated the association between BZDs use and cancer risk of people aged over 20 years. During the study period, 42,500 cases diagnosed with cancer were identified and analyzed for BZDs use. For each case, six eligible controls matched for age, sex, and the index date (ie, free of any cancer in the date of case diagnosis) by using propensity score. For appropriate risk estimation, we observed the outcomes according to their length of exposure (LOE) and defined daily dose (DDD). To mimic bias, we adjusted with potential confounding factors such as medications and comorbid diseases which could influence for cancer risk during the study period. The data was analyzed by using Cox proportional hazard regression and conditional logistic regression.The finding unveils benzodiazepines use into safe and unsafe groups for their carcinogenicity. The use of diazepam (HR, 0.96; 95%CI, 0.92-1.00), chlorodizepoxide (HR, 0.98; 95%CI, 0.92-1.04), medazepam (HR, 1.01; 95%CI, 0.84-1.21), nitrazepam (HR, 1.06; 95%CI, 0.98-1.14), oxazepam (HR, 1.05; 95%CI, 0.94-1.17) found safer among BZDs. However, clonazepam (HR, 1.15; 95%CI, 1.09-1.22) were associated with a higher risk for cancers. Moreover, specific cancer risk among BZDs use was observed significantly increased 98% for brain, 25% for colorectal, and 10% for lung, as compared with non-BZDs use.Diazepam, chlordiazepoxide, medazepam, nitrazepam, and oxazepam are safe among BZDs use for cancer risk. Our findings could help physicians to select safer BZDs and provide an evidence on the carcinogenic effect of benzodiazepines use by considering the LOE and DDD for further research.

Self-administration of clonidine, oxazepam, and hydromorphone by patients undergoing methadone detoxification.

The extent to which hydromorphone, clonidine, and oxazepam alleviate the symptoms of opioid withdrawal and the extent and pattern of self-administration of these drugs during methadone detoxification were examined within a residential laboratory in three groups of patients dependent on methadone. Six times over the course of detoxification, acute effects of orally administered placebo and a single active drug (hydromorphone HCl, 3 mg, clonidine HCl, 0.3 mg, or oxazepam, 30 mg, all given twice daily) were tested, followed by an opportunity for subjects to self-administer the drug and dose of their choice. Hydromorphone significantly decreased opioid withdrawal symptoms and was more preferred for self-administration than the placebo. Clonidine and oxazepam did not significantly decrease withdrawal symptoms, nor was either drug self-administered significantly more than placebo. Clonidine, however, did induce side effects.

Pharmacologic treatment of noncognitive behavioral disturbances in elderly demented patients.

Fifty-nine elderly residents of long-term care facilities who had DSM-III diagnoses of dementia were studied in an 8-week randomized, double-blind comparison trial of haloperidol, oxazepam, and diphenhydramine to test the efficacy of these agents in the treatment of clinically significant behavioral disturbances in patients with dementia. All three agents demonstrated modest but significant efficacy as measured by clinician ratings of agitated behavior and activities of daily living. The absolute magnitude of improvement was greater for haloperidol and diphenhydramine than for oxazepam, but differences among groups did not approach statistical significance. Frequencies of acute adverse events during the trial were similar across the drug treatment groups. Although these drugs may differ in terms of long-term safety and efficacy, they appear to be equivalent for short-term management of agitated behavior in severely demented patients.

Pharmacokinetics of zidovudine alone and in combination with oxazepam in the HIV infected patient.

This three-phase study was designed to determine if a pharmacokinetic drug-drug interaction exists between zidovudine and oxazepam. Six individuals infected with human immunodeficiency virus (HIV) and receiving zidovudine at 500 mg daily, with normal renal and hepatic function, were enrolled. During phase I, zidovudine pharmacokinetics were studied after steady-state oral administration (100 mg every 4 h) and after a single dose (70 mg) of intravenous zidovudine. Phase II consisted of a single oral dose (30 mg) of oxazepam followed by a 48-h blood sampling period. Phase III began with 48 h of concomitant zidovudine, 100 mg orally every 4 h, and oxazepam, 15 mg orally every 8 h, followed by concomitant dosing of intravenous zidovudine and oral oxazepam. Zidovudine concentrations were determined by radioimmunoassay. Oxazepam concentrations were determined with use of a fluorescence polarization immunoassay. The calculated bioavailability was 0.61 for zidovudine alone and 0.75 when administered in combination with oxazepam (p = 0.16). Plasma half-life for oral zidovudine alone and in combination with oxazepam was 1.17 h versus 0.99 h, respectively (p = 0.25), and 1.38 h versus 1.15 h (p = 0.38) for intravenous zidovudine during single and combination therapy, respectively. Total body clearance of zidovudine was not significantly altered by oxazepam (93 L/h vs. 109 L/h, p = 0.16). The mean pharmacokinetic parameters determined for a single 30-mg dose of oxazepam for oral clearance, apparent volume of distribution, and plasma half-life were 9.8 L/h, 65.7 L, and 5.1 h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzodiazepine withdrawal effects.

1. Twenty-nine patients with anxiety neurosis who had completed a one week placebo, three week active drug study on either halazepam or oxazepam were observed for eight weeks for withdrawal effects. Half of the patients received a placebo for the first two weeks of the withdrawal study and half had all medication abruptly stopped. 2. There was no significant difference in the pattern of withdrawal between halazepam, an intermediate range benzodiazepine, and oxazepam, a short acting benzodiazepine. 3. Withdrawal symptoms were apparent, maximally between week 1 and 2 together with possible rebound effects. 4. Patients who received placebo had significantly less severe withdrawal symptoms than those who had their medication abruptly discontinued.

An examination of differences in the time course of oxazepam's effects on implicit vs explicit memory.

The present study was designed to examine the effects of oxazepam on implicit vs explicit memory processes, as a function of this drug's time course. The effects of oxazepam (30 mg) or placebo on directly comparable tests of implicit memory (word stem completion) and explicit memory (cued recall) were examined at three time points: 100 min post-drug administration (prior to the theoretical peak plasma concentration of oxazepam; i.e.'pre-peak' condition), 170 min post-drug (close to theoretical peak; i.e. 'peak' condition) or 240 min post-drug (following theoretical peak: i.e. 'post-peak' condition). Sixty healthy volunteers were randomly assigned to either the drug condition or the placebo condition in a double-blind design and were tested on both memory tests at one of the three time points. In the 'pre-peak' condition, oxazepam impaired cued recall performance relative to placebo but did not impair priming. In the 'peak' condition, oxazepam impaired performance on both memory tasks. In the 'post-peak' condition, cued recall performance in the oxazepam group remained significantly impaired relative to placebo. However, oxazepam-induced impairments in priming were only marginal, suggesting that oxazepam-induced impairments in implicit memory processes begin to wane following theoretical peak drug concentrations. The fact that oxazepam-induced priming impairments were significant only when the word stem completion task was administered close to peak plasma concentrations, supports the hypothesis that benzodiazepines exert time-dependent effects on implicit memory processes. The results also support the theoretical distinction between implicit and explicit memory processes, since the directly comparable implicit and explicit tasks showed different impairment curves over time.