Acute lead poisoning: a diagnostic challenge in the emergency department.

Acute abdominal pain is a common presentation to the emergency department (ED). Ruling out life-threatening causes and giving pain relief are the most important tasks in ED. We describe a 32-year-old man who presented to ED with abdominal pain and vomiting which was unrelieved by usual doses of analgesic. Extensive investigations revealed no significant abnormalities. On further probing, he admitted taking traditional medications for infertility. The toxicological panel revealed a high blood lead level, leading to a diagnosis of acute lead toxicity. Chelation therapy with D-penicillamine was initiated and the patient's abdominal pain resolved within 4 days.

A 'symptom-triggered' approach to alcohol withdrawal management.

In acute hospital settings, alcohol withdrawal often causes significant management problems and complicates a wide variety of concurrent conditions, placing a huge burden on the NHS. A significant number of critical incidents around patients who were undergoing detoxification in a general hospital setting led to the need for a project to implement and evaluate an evidence-based approach to the management of alcohol detoxification-a project that included a pre-intervention case note audit, the implementation of an evidence-based symptom-triggered detoxification protocol, and a post-intervention case note audit. This change in practice resulted in an average reduction of almost 60% in length of hospital stay and a 66% reduction in the amount of chlordiazepoxide used in detoxification, as well as highlighting that 10% of the sample group did not display any signs of withdrawal and did not require any medication. Even with these reductions, no patient post-intervention developed any severe signs of withdrawal phenomena, such as seizures or delirium tremens. The savings to the trust (The Pennine Acute Hospital Trust) are obvious,but the development of a consistent, quality service will lead to fewer long-term negative effects for patients that can be caused by detoxification. This work is a project evaluation of a locally implemented strategy, which, it was hypothesised,would improve care by providing an individualised treatment plan for the management of alcohol withdrawal symptoms.

Trends in anxiolytic-hypnotic use and polypharmacy in Taiwan, 2002-2009: a nationwide, population-based survey.

OBJECTIVES: Use of anxiolytics-hypnotics, including benzodiazepines and "z" hypnotics, is a public health concern. This study aimed to investigate the trends in prevalence of anxiolytic-hypnotic drug use and polypharmacy (simultaneous use of two or more anxiolytics-hypnotics) in Taiwan. METHODS: A dynamic sample of one million individuals who were randomly selected from the National Health Insurance database was used to detect populationwide trends in the use of anxiolytics-hypnotics in Taiwan between 2002 and 2009. The analyses included drugs that are administered orally, intravenously, or intramuscularly as well as single or compound drugs. The authors identified the number of individuals who used the drugs, the sum of days of reported drug use for all individuals (person-days), and the distribution of anxiolytic-hypnotic polypharmacy for all claims for ambulatory, pharmacy, and hospital care. RESULTS: Annual prevalence of any anxiolytic-hypnotic use in Taiwan was higher than 20%. The number of person-days greatly increased from 2002 (4.0%) to 2009 (6.6%). The increases in use between 2002 and 2009 were greatest for clonazepam (prevalence, 7% versus 1.8%; person-days, .2% versus .6%) and zolpidem (prevalence, 2.4% versus 4.2%; person-days, .5% versus 1.5%). Polypharmacy accounted for almost 70% of all person-days of anxiolytic-hypnotic use. CONCLUSIONS: This nationwide, population-based survey presents real-world epidemiological evidence about anxiolytic-hypnotic use. The adverse effects of the long-term use of anxiolytics-hypnotics have been established, and unnecessary use of these drugs, particularly in polypharmacy regimens, should be avoided.

Unplanned alcohol withdrawal: a survey of consecutive admissions to an acute medical unit in 2010 and 2011.

BACKGROUND: Alcohol-related presentations to hospital have been increasing in the UK in recent years, including the occurrence of acute withdrawal. This study sought to better characterize the clinical features, patterns of treatment and outcomes in this patient group. METHODS: Patients admitted to the Acute Medical Unit of York Hospital due to acute alcohol withdrawal are normally treated according to a protocol that involves both fixed-dose and symptom-triggered drug administration. Admissions between 2010 and 2011 inclusive were studied. RESULTS: There were 211 admission episodes solely due to acute alcohol withdrawal, involving 127 patients (97 men, 76.4%) with median age of 45 years (interquartile range: 39-52 years). There was a high prevalence of depression (34%), alcoholic liver disease (22%) and drug misuse (12%). Total dose of chlordiazepoxide varied between 0 and 610 mg and tapered rapidly after the first day of admission. Vitamin supplements were administered to >90% of patients, including parenteral and oral in 74%, parenteral alone in 9% and oral alone in 9%. A specialist alcohol nurse reviewed patients while in hospital in 40% of cases. Approximately one-third of patients had multiple admissions for alcohol withdrawal during the study period. CONCLUSION: A high prevalence of physical and mental health disorders was observed. The local policy permitted high initial chlordiazepoxide doses and prompt downward titration, with a broad range of doses between individuals. Approximately 10% required no specific therapy, and there may be opportunities for developing alternative pathways for delivery of care in an ambulatory setting for these patients.

Pharmacology of neuropeptide S in mice: therapeutic relevance to anxiety disorders.

RATIONALE: Neuropeptide S (NPS) and its receptor (NPSR) comprise a recently deorphaned G protein-coupled receptor system. Recent reports implicate NPS in the mediation of anxiolytic-like activity in rodents. OBJECTIVES: To extend the characterization of NPS, the present studies examined the in vitro pharmacology of mouse NPSR and the in vivo pharmacology of NPS in three preclinical mouse models predictive of anxiolytic action: the four-plate test (FPT), elevated zero maze (EZM), and stress-induced hyperthermia (SIH). The ability of NPS to produce antidepressant-like effects in the tail suspension test (TST) was also investigated. RESULTS: In vitro, mouse NPS 1-20 (mNPS 1-20) and the C-terminal glutamine-truncated mouse NPS 1-19 bound mNPSR with high affinity (Ki = 0.203 +/- 0.060, 0.635 +/- 0.141 nM, respectively) and potently activated intracellular calcium release (EC50 = 3.73 +/- 1.08, 4.10 +/- 1.25 nM). NPS produced effects in vivo consistent with anxiolytic-like activity. In FPT, NPS increased punished crossings (minimal effective dose [MED]: mNPS 1-20 = 0.2 microg, mNPS(1-19) = 0.02 microg), similar to the reference anxiolytic, alprazolam (MED 0.5 microg). NPS increased the percentage of time spent in the open quadrants of EZM (MED: mNPS 1-20 = 0.1 microg, mNPS 1-19 = 1.0 microg), like the reference anxiolytic, chlordiazepoxide (MED 56 microg). In SIH, NPS attenuated stress-induced increases in body temperature similar to alprazolam but with a large potency difference between the NPS peptides (MED: mNPS 1-20 = 2.0 microg, mNPS 1-19 = 0.0002 microg) and mNPS 1-20 increased baseline temperature. Unlike fluoxetine, NPS did not effect immobility time in TST, indicating a lack of antidepressant-like activity. CONCLUSIONS: These data provide an important confirmation and expansion of the anxiolytic-like effects of NPS and implicate the NPS system as a novel target for anxiolytic drug discovery.

Effects of chlordiazepoxide on footshock- and corticotropin-releasing factor-induced increases in cortical and hypothalamic norepinephrine secretion in rats.

Noradrenergic and corticotropin-releasing factor (CRF) neuronal systems within the brain have been implicated in stress and anxiety. Synaptic release of cerebral norepinephrine (NE) is increased during stress, and following intracerebral CRF administration. Benzodiazepines are commonly used anxiolytic drugs but information on their effects on the stress- and CRF-related release of NE is limited. We have used in vivo microdialysis to test the effects of the benzodiazepine, chlordiazepoxide (CDP) on the noradrenergic responses to footshock and intracerebroventricular CRF in the medial hypothalamus and the medial prefrontal cortex (PFM) of freely moving rats. Footshock (60 x 0.1-0.2 mA shocks in 20 min) significantly increased microdialysate concentrations of NE in the first sample collected after initiating the footshock. In the hypothalamus, microdialysate NE was augmented 64% above baseline. A second footshock session (100 min after the first footshock) increased microdialysate NE to 313% of the baseline. Thus the noradrenergic responses to footshock were enhanced by preceding footshocks. CRF (100 ng) administered into the locus coeruleus (LC) almost tripled microdialysate concentrations of NE in the PFM. CDP (5mg/kg, i.p.) had no statistically significant effects on the basal dialysate concentrations of NE, but it significantly attenuated both footshock- and CRF-induced increases in dialysate NE. CDP may exert a direct inhibitory effect on the noradrenergic neurons, alter the input to LC noradrenergic neurons, or alter the ability of CRF to activate the LC noradrenergic system.

Anxiolytic effects of lavender oil inhalation on open-field behaviour in rats.

To establish a valid animal model of the effects of olfactory stimuli on anxiety, a series of experiments was conducted using rats in an open-field test. Throughout, effects of lavender oil were compared with the effects of chlordiazepoxide (CDP), as a reference anxiolytic with well-known effects on open-field behaviour. Rats were exposed to lavender oil (0.1-1.0 ml) for 30 min (Experiment 1) or 1h (Experiment 2) prior to open-field test and in the open field or injected with CDP (10 mg/kg i.p.). CDP had predicted effects on behaviour, and the higher doses of lavender oil had some effects on behaviour similar to those of CDP. In Experiment 3, various combinations of pre-exposure times and amounts of lavender oil were used. With sufficient exposure time and quantity of lavender the same effects were obtained as in Experiment 2. Experiment 4 demonstrated that these behavioural effects of lavender could be obtained following pre-exposure, even if no oil was present in the open-field test. In Experiments 2-4, lavender oil increased immobility. Together, these experiments suggest that lavender oil does have anxiolytic effects in the open field, but that a sedative effect can also occur at the highest doses.

Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social-separation-stress procedure.

Piper methysticum extract (Kava kava) possesses anxiolytic properties. However, it is unknown whether these effects are best predicted by total kavalactone content or by one or more of its primary kavalactone constituents. Using the chick social separation-stress procedure as an anxiolytic bioassay, P. methysticum samples containing 12.8-100.0% total kavalactones (Exp. 1) and fractions containing 1-6 kavalactones of varying concentrations (0.1-67.5%; Exps. 2-3) were screened for activity and compared against a 5.0 mg/kg dose of chlordiazepoxide (CDP; Exp. 3). Eight-day-old chicks received IP injections of either vehicle or test compounds 30 min before being placed in the presence of two conspecifics or in isolation for a 3 min observation period. Dependent measures were ventral recumbency latency (sedation), distress vocalizations, and a measure of stress-induced analgesia (in Exps. 1 and 2 only). P. methysticum extract samples attenuated distress vocalizations in a concentration-dependent manner. The P. methysticum fraction that contained the highest concentration of dihydrokavain attenuated distress vocalizations in a manner equivalent to that of CDP. The extract samples and fractions that possessed anxiolytic properties did not possess the sedative properties found in CDP. Collectively, these findings suggest that dihydrokavain may be necessary and sufficient in mediating the anxiolytic properties of P. methysticum extract.

Anxiolytic effects of kava extract and kavalactones in the chick social separation-stress paradigm.

RATIONALE: Piper methysticum extract (kava kava) possesses numerous therapeutic properties, but it is unknown which of its principle constituents (kavalactones) subserve such effects. OBJECTIVES: This experiment sought to characterize the putative anxiolytic properties of P. methysticum extract and its six principle kavalactones in the chick social separation-stress paradigm. METHODS: Eight-day-old chicks received intraperitoneal injections of either vehicle, chlordiazepoxide (5.0 mg/ml per kg), P. methysticum extract (containing 30% kavalactones), kavain, dihydrokavain, methysticin, dihydromethysticin, yangonin, or desmethoxyyangonin (30 mg/ml per kg for kava compounds) 30 min prior to being tested in the presence of two conspecifics or in isolation for a 3-min observation period. Latency to adopt a ventral recumbent posture to index sedation, number of vocalizations to index separation distress, and a composite pain score (in response to 50 microliters 0.10% formalin injection into the plantar surface of the foot) to index stress-induced analgesia served as dependent measures. RESULTS: Both chlordiazepoxide and P. methysticum extract attenuated separation-induced distress vocalizations and stress-induced analgesia. Dihydrokavain attenuated separation-induced distress vocalizations. CONCLUSIONS: These findings suggest that the anxiolytic effects of P. methysticum extract may be mediated, in part, by dihydrokavain.

Anticonvulsant effect of water extract of Scutellariae radix in mice.

Since a previous study indicated that the water extract of Scutellariae radix (SR) had high affinity for the benzodiazepine (BDZ) binding site of GABA(A) receptors, the present study examined whether SR water extract has an anticonvulsant effect in vivo and an enhancing effect on gamma-amino-n-butyric acid (GABA)-stimulated uptake of 36Cl(-) in cortex preparation in vitro in mice. The results showed that SR water extract had little effect on pentylenetetrazol (PTZ, 85 mg/kg, s.c.)-induced clonic seizures but significantly inhibited maximal electroshock-induced tonic seizures with an ED(50) of 3.6 g/kg. The BDZ agonist chlordiazepoxide (10 mg/kg, i.p.) had anticonvulsant activity on both types of seizures. In 36Cl(-) uptake assay, SR water extract (1-500 microg/ml) had no significant effect on 25 microM GABA-stimulated 36Cl(-) uptake, whereas chlordiazepoxide (10 microM) increased the 36Cl(-) uptake to 125% of control. Therefore, the present results showed for the first time that SR water extract had anticonvulsant activity against maximal electroshock-induced tonic seizures, and suggested that this anticonvulsant effect might be not via the activation of the BDZ binding site of GABA(A) receptors, but probably via the prevention of seizure spread.

[Influence of stress and stress-protecting factors on rat tolerance to cold and efficiency of rat adaptation to cold]. / Vliianie stressa i stress-protektivnykh faktorov na kholodovuiu ustoichivost' i éffektivnost' adaptatsii krys k kholodu.

The adaptive characteristics of the body, including the specific features of increased cold resistance upon repeated exposures to cold, are determined not only by the properties of thermogenic structures themselves, but largely depend on the contribution of the central mechanisms which control the processes of habituation and mobilization of functions. The experiments revealed an increase in cold resistance in rats after preexposure to cold. Immobilization stress prior to training cold significantly decreased rapid cold resistance in the animals, but increased the training effect of the first cooling. On the contrary, chlordiazepoxide increased cold resistance during the first cooling. Testing of the untreated animal showed no effect of training. No adaptive changes in cold resistance occurred in rats with impaired amygdaloid complex. Analyzing adrenal catecholamines revealed a significant elevation of dopamine concentrations in the rats exposed to cold. Hypothalamic catecholamines did not change with cold and serotonin in intact rats and 5-hydroxyindoleacetic acid in amygdalectomized rats substantially increased.

[The effect of nifedipine and chlordiazepoxide on alcohol withdrawal syndrome]. / Ocena efektów dzialania nifedypiny i chlordiazepoksydu w alkoholowym zespole abstynencyjnym (AZA).

The aim this study was to evaluate the efficacy and tolerability of DHP calcium channel antagonist-nifedipine in human AWS in comparison to conventional treatment with chlordiazepoxide. Fifty nine hospitalized alcoholics of both sexes with diagnosis of AWS according to DSM-III-R criteria were treated for 2 weeks in monotherapy with nifedipine (Cordafen-Polfa)-60 mg/d. or with chlordiazepoxide (Elenium-Polfa)-150 mg/d. Evaluation of AWS symptoms was performed at baseline and after 3, 7, 14 days using Sandowal-Wang scale. Our original scales (37 items) were designed for measuring the depth of dependence (WGU) and the velocity of dependence syndrome appearance (WWO). The results show that both groups were similar regarding WGU and WWO before treatment. Both drugs caused an improvement of AWS symptoms after 3 and 7 days lasting till the end of hospitalization. Nifedipine was well tolerated and no side effects were observed or reported. The group and multidimensional analyses were performed using original computer program. The patients were divided into 3 subgroups. Comparison of mean values of improvement index between both drugs in those subgroups of patients according to WGU criteria, revealed that nifedipine was more effective on the 3-rd and 7-th day in 3 groups and 2 groups resp. According to WWO criteria the improvement index was significantly higher on the 3-rd and 7-th day in two groups whereas in one group chlordiazepoxide and nifedipine action was equal. The proposed method of group and multidimensional analysis enable us to compare the effectiveness of different kinds of AWS treatment. It is an useful aid of choosing the best drug treatment for a new patient.

[The neurochemical profile of the dorsal hippocampus and the antiaversive effects of anxiolytics in different models of anxiety in rats]. / Neirokhimicheskii profil' dorzal'nogo gippokampa i antiaversivnye éffekty anksiolitikov v razlichnykh modeliakh trevogi u krys.

Chemical stimulation of the dorsal hippocampus by serotonin and GABA decreases anxiety in a test of avoidance of precarious situation but not of illuminated platform. Intrahippocampal injection of chlordiazepoxide induced similar effect. Microinjection of glutamic acid into the hippocampus increases and that of dopamine decreases anxiety in the test of avoidance of illuminated platform but not of precarious situation. Ipsapiron locally injected unto the dorsal hippocampus induces antiaversive effect counteracting anxiety states in both behavioural models. A conclusion is drown that hippocampal monoanin- and acidergic mechanisms are functionally different in anxiety of different modes of aversive origin. Differences in spectra of anxiolytic action of chlordiazepoxide and ipsapiron may be underlied by nonsimilar degree of involvement of these transmitter mechanisms in anxiety states being formed by aversive influences of different biological significance.

[The role of monoamin- and acidergic mechanisms of the hippocampus in anxiety states of different origins and their participation in the antiaversive effects of anxiolytics]. / O roli monoamin- i atsidergicheskikh mekhanizmov gippokampa v sostoianii trevogi razlichnogo geneza i ob ikh uchastii v antiaversivnykh éffektakh anksiolitikov.

The experiments on rats with tests of avoiding "lighting square" and "threatening situation" and with the chemical stimulation of dorsal and ventral hippocampus with dopamine, 5-HT, GABA and glutamine acid, showed different functional significance of these monoamines and acidergic transmitters agents in the states of anxiety of heteromodal aversive genesis. It seems that the variations in the action spectrum of anxiolytics under study are due to unequal degree of 5-HT and GABA-ergic transmitter mechanisms of dorsal and ventral hippocampus.

Effects of nitrendipine, chlordiazepoxide, flumazenil and baclofen on the increased anxiety resulting from alcohol withdrawal.

1. Male hooded Lister rats were fed a liquid diet containing 10% absolute ethanol for 4-5 weeks. Control rats received the liquid diet in amounts controlled to produce equal weight gain. 2. The rats were tested 7.5 h after withdrawal of ethanol and 30 min after i.p. injection with nitrendipine, chlordiazepoxide or baclofen or 20 min after i.p. injection with flumazenil. 3. Nitrendipine (25-100 mg/kg) was unable to reverse the anxiogenic responses detected on withdrawal from ethanol, but the highest dose did reduce withdrawal tremor. 4. Chlordiazepoxide (10 mg/kg), flumazenil (4 mg/kg) and baclofen (1.25 mg/kg) significantly reversed the anxiogenic response detected on withdrawal from ethanol. 5. These reversals of ethanol withdrawal responses are similar to the reversal of the increased anxiety detected on withdrawal from chronic treatment with benzodiazepines. 6. The mechanisms and clinical implications of these drug-induced reversals are discussed.

Irritable bowel syndrome: therapeutic evaluation of indigenous drugs.

Among 169 patients with irritable bowel syndrome (IBS), standard therapy (with clidinium bromide, chlordiazepoxide and isaphaghulla), a compound Ayurvedic preparation (with Aegle marmelos correa plus Bacopa monniere Linn) along with a matching placebo were given in a double blind randomised trial for 6 wk. The Ayurvedic preparation in 57 patients was found effective in 64.9 per cent, while standard therapy (60 patients) was useful in 78.3 per cent. Patients on placebo (52 patients) showed improvement in 32.7 per cent only. Ayurvedic therapy was particularly beneficial in diarrhoea predominant form as compared to placebo. The standard therapy was more useful in the painful form of IBS as compared to placebo and Ayurvedic preparation. In gas predominant form the effect of standard as well as Ayurvedic therapy, was similar to placebo. Long-term follow-up (greater than 6 months) showed that both forms of therapy were no better than placebo in limiting the relapse.

Self-control, biofeedback, and change in 'psychosomatic' approach.

The new psychosomatic treatment modalities of biofeedback and relaxation techniques have in common an emphasis on self-control or self-regulation. The surging popularity of the self-control techniques at present may reflect a change in the self-image of medicine, which emphasizes its role as a collaborator of the patient in his self-control of disease processes. The modern concept of psychosomatic medicine emphasizes a systems or field approach to evaluation and treatment rather than 'psychogenic' causes of physical illness. The self-control treatment modalities form an important part of the armamentaria of a modern 'psychosomaticist'. We present preliminary data suggesting that 'potentiation' of biofeedback treatment may be useful. In borderline hypertensives, using pharmacologic means to reduce blood pressure during a biofeedback session may help subjects identify and re-create the 'low blood pressure states' without further aid of drugs. Hypertensives seeking biofeedback treatment are extremely internal in locus of control and tend to generalize their self-control to other areas of life to foster health and to prevent illness.

[Psychophysiologic characteristics of the individual psychotropic activity of benzodiazepine derivatives under experimental conditions]. / Psikhofiziologicheskaia kharakteristika individual'noi psikhotropnoi aktivnosti benzodiazepinovykh proizvodnykh v usloviiakh éksperimenta.

In 156 experiments performed on 41 cats with adequate experimental models of pseudoneurotic conditions, states of anxiety due to an electrostimulation of the hypothalamus through implanted electrodes and an emotional stress due to a conflict situation the authors compared the individual traits of the psychotropic activity of lorazepam, diazepam, chlordiazepoxide, oxazepam, nirazepam. These experiments permitted to display significant differences of psychophysiological structures in the tranquilizing effect of 5 benzodiazepine derivatives.

A study in mice of benzodiazephine-anticholinergic interaction: protection against restraint-immersion and forced exertion-induced gastric mucosal erosion.

The effectiveness of benzodiazepines and anticholinergics administered alone or in combination in preventing restraint-immersion and forced exertion-induced gastric mucosal erosion was investigated in mice. The benzodiazepines used were diazepam and chlordiazepoxide HCI and the anticholinergics were propantheline bromide and clidinium bromide. The administratio of a benzodiazepine with an anticholinergic resulted in additive or supra-additive protective effects in both systems. In the restraint-immersion system, diazepam combined with propantheline bromide at a ratio of 1 to 13.7 yielded a 4.53-fold supra-additive effect. At ratios of 4.6 or 1.5 parts of propantheline bromide to 1 part of diazepam an additive effect was observed. One part of diazepam, when combined with 1.4 to 12.0 parts of clidinium bromide resulted in supra-additive effects of about 1.5-fold. The co-administration of chlordiazepoxide HCI and clidinium bromide in ratios of 2 to 1 or 2.5 to 1 resulted in supra-additive effects of 2.4- and 1.85-fold, respectively. At higher and lower ratios additive effects were demonstrated. In the forced exertion system, diazepam combined with either anticholinergic resulted in supra-additive effects of 2- to 3-fold which occurred at ratios of diazepam to the anticholinergic varying over an 8-fold range. The co-administration of 2 parts of chlordiazepoxide HCI and 1 part of clidinium bromide resulted in a 2.84-fold supra-additive effect in the forced exertion system. These results are discussed in relation to the use of benzodiazepine anticholinergic combinations in the treatment of human gastric and duodenal ulcer disease.