text:
|1.1 Substance
|1.2 Group
|1.3 Synonyms
|1.4 Identification numbers
|1.4.1 CAS number
|1.4.2 Other numbers
|1.5 Main brand names, main trade names
|1.6 Main manufacturers, main importers
|2.1 Main risks and target organs
|2.2 Summary of clinical effects
|2.3 Diagnosis
|2.4 First aid measures and management principles
|3.1 Origin of the substance
|3.2 Chemical structure
|3.3 Physical properties
|3.3.1 Colour
|3.3.2 State/Form
|3.3.3 Description
|3.4 Other characteristics
|3.4.1 Shelf-life of the substance
|3.4.2 Storage conditions
|4.1 Indications
|4.1.1 Indications
|4.1.2 Description
|4.2 Therapeutic dosage
|4.2.1 Adults
|4.2.2 Children
|4.3 Contraindications
|5.1 Oral
|5.2 Inhalation
|5.3 Dermal
|5.4 Eye
|5.5 Parenteral
|5.6 Other
|6.1 Absorption by route of exposure
|6.2 Distribution by route of exposure
|6.3 Biological half-life by route of exposure
|6.4 Metabolism
|6.5 Elimination and excretion
|7.1 Mode of action
|7.1.1 Toxicodynamics
|7.1.2 Pharmacodynamics
|7.2 Toxicity
|7.2.1 Human data
|188.8.131.52 Adults
|22.214.171.124 Children
|7.2.2 Relevant animal data
|7.2.3 Relevant in vitro data
|7.3 Carcinogenicity
|7.4 Teratogenicity
|7.5 Mutagenicity
|7.6 Interactions
|7.7 Main adverse effects
|8.1 Material sampling plan
|8.1.1 Sampling and specimen collection
|22.214.171.124 Toxicological analyses
|126.96.36.199 Biomedical analyses
|188.8.131.52 Arterial blood gas analysis
|126.96.36.199 Haematological analyses
|126.96.36.199 Other (unspecified) analyses
|8.1.2 Storage of laboratory samples and specimens
|220.127.116.11 Toxicological analyses
|18.104.22.168 Biomedical analyses
|188.8.131.52 Arterial blood gas analysis
|22.214.171.124 Haematological analyses
|22.214.171.124 Other (unspecified) analyses
|8.1.3 Transport of laboratory samples and specimens
|22.214.171.124 Toxicological analyses
|184.108.40.206 Biomedical analyses
|18.104.22.168 Arterial blood gas analysis
|22.214.171.124 Haematological analyses
|184.108.40.206 Other (unspecified) analyses
|8.2 Toxicological Analyses and Their Interpretation
|8.2.1 Tests on toxic ingredient(s) of material
|22.214.171.124 Simple Qualitative Test(s)
|22.214.171.124 Advanced Qualitative Confirmation Test(s)
|188.8.131.52 Simple Quantitative Method(s)
|18.104.22.168 Advanced Quantitative Method(s)
|8.2.2 Tests for biological specimens
|22.214.171.124 Simple Qualitative Test(s)
|126.96.36.199 Advanced Qualitative Confirmation Test(s)
|18.104.22.168 Simple Quantitative Method(s)
|184.108.40.206 Advanced Quantitative Method(s)
|22.214.171.124 Other Dedicated Method(s)
|8.2.3 Interpretation of toxicological analyses
|8.3 Biomedical investigations and their interpretation
|8.3.1 Biochemical analysis
|220.127.116.11 Blood, plasma or serum
|188.8.131.52 Urine
|188.8.131.52 Other fluids
|8.3.2 Arterial blood gas analyses
|8.3.3 Haematological analyses
|8.3.4 Interpretation of biomedical investigations
|8.4 Other biomedical (diagnostic) investigations and their interpretation
|8.5 Overall interpretation of all toxicological analyses and toxicological investigations
|8.6 References
|9.1 Acute poisoning
|9.1.1 Ingestion
|9.1.2 Inhalation
|9.1.3 Skin exposure
|9.1.4 Eye contact
|9.1.5 Parenteral exposure
|9.1.6 Other
|9.2 Chronic poisoning
|9.2.1 Ingestion
|9.2.2 Inhalation
|9.2.3 Skin exposure
|9.2.4 Eye contact
|9.2.5 Parenteral exposure
|9.2.6 Other
|9.3 Course, prognosis, cause of death
|9.4 Systematic description of clinical effects
|9.4.1 Cardiovascular
|9.4.2 Respiratory
|9.4.3 Neurological
|184.108.40.206 Central nervous system (CNS)
|22.214.171.124 Peripheral nervous system
|188.8.131.52 Autonomic nervous system
|184.108.40.206 Skeletal and smooth muscle
|9.4.4 Gastrointestinal
|9.4.5 Hepatic
|9.4.6 Urinary
|188.8.131.52 Renal
|220.127.116.11 Other
|9.4.7 Endocrine and reproductive systems
|9.4.8 Dermatological
|9.4.9 Eye, ear, nose, throat: local effects
|9.4.10 Haematological
|9.4.11 Immunological
|9.4.12 Metabolic
|18.104.22.168 Acid-base disturbances
|220.127.116.11 Fluid and electrolyte disturbances
|126.96.36.199 Others
|9.4.13 Allergic reactions
|9.4.14 Other clinical effects
|9.4.15 Special risks
|9.5 Other
|9.6 Summary
|10.1 General principles
|10.2 Life supportive procedures and symptomatic/specific treatment
|10.3 Decontamination
|10.4 Enhanced elimination
|10.5 Antidote treatment
|10.5.1 Adults
|10.5.2 Children
|10.6 Management discussion
|11.1 Case reports from literature
|12. Additional information
|12.1 Specific preventive measures
|12.2 Other
Chlordiazepoxide hydrochloride International Programme on Chemical Safety Poisons Information Monograph 321 Pharmaceutical This monograph does not contain all of the sections completed. This mongraph is harmonised with the Group monograph on Benzodiazepines (PIM G008). 1. NAME 1.1 Substance
Chlordiazepoxide hydrochloride1.2 Group ATC classification index Psycholeptics(N05)/ Anxiolytics(N05B)/ Benzodiazepine derivatives(N05BA) 1.3 Synonyms Chlordiazepoxidi Hydrochloridum; Methaminodiazepoxide Hydrochloride; NSC-115748; Ro-5-0690; clopoxide1.4 Identification numbers 1.4.1 CAS number 1.4.2 Other numbers 1.5 Main brand names, main trade names 438-41-5 Helogaphen; Libritabs; Multum; Risolid; Silibrin; Tropium; Ansiacal; A-Poxide; Balance; Benzodiapin; Cebrum; Corax; Disarim; Elenium; Equibral; Labican; Lentotran; Librium; O.C.M.; Psichial; Psicoterina; Reliberan; Seren Vita; SK-Lygen; Viansin1.6 Main manufacturers, main importers 2. SUMMARY 2.1 Main risks and target organs Central nervous system, causing depression of respiration and consciousness.2.2 Summary of clinical effects Central nervous system (CNS) depression and coma, or paradoxical excitation, but deaths are rare when benzodiazepines are taken alone. Deep coma and other manifestations of severe CNS depression are rare. Sedation, somnolence, diplopia, dysarthria, ataxia and intellectual impairment are the most common adverse effects of benzodiazepines. Overdose in adults frequently involves co- ingestion of other CNS depressants, which act synergistically to increase toxicity. Elderly and very young children are more susceptible to the CNS depressant action. Intravenous administration of even therapeutic doses of benzodiazepines may produce apnoea and hypotension.2.3 Diagnosis Dependence may develop with regular use of benzodiazepines, even in therapeutic doses for short periods. If benzodiazepines are discontinued abruptly after regular use, withdrawal symptoms may develop. The amnesia produced by benzodiazepines can have medico-legal consequences. The clinical diagnosis is based upon the history of benzodiazepine overdose and the presence of the clinical signs of benzodiazepine intoxication.2.4 First aid measures and management principles Benzodiazepines can be detected or measured in blood and urine using standard analytical methods. This information may confirm the diagnosis but is not useful in the clinical management of the patient. A clinical response to flumazenil, a specific benzodiazepine antagonist, also confirms the diagnosis of benzodiazepine overdose, but administration of this drug is rarely justified. Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly involve co- ingestion of other CNS depressants and other drugs. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. The routine use of flumazenil is contraindicated because of potential complications, including seizures. Renal and extracorporeal methods of enhanced elimination are not effective.3. PHYSICO-CHEMICAL PROPERTIES 3.1 Origin of the substance 3.2 Chemical structure Chlordiazepoxide hydrochloride Chemical name: 7-Chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-amine 4- oxide hydrochloroide; Alternative 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide hydrochloride; Molecular Formula: C16H14ClN3O,HCl Molecular Weight: 336.2 Chlordiazepoxide Chemical name: 7-Chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-amine 4- oxide; Alternative 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4- oxide; Molecular formula: C16H14ClN3O. Molecular weight: 299.763.3 Physical properties 3.3.1 Colour Odourless white or slightly yellow3.3.2 State/Form Solid-crystals3.3.3 Description Soluble in water; soluble or sparingly soluble in alcohol; practically insoluble in chloroform, in ether, and in petroleum spirit.3.4 Other characteristics 3.4.1 Shelf-life of the substance 3.4.2 Storage conditions A 1% solution of sterile Chlordiazepoxide Hydrochloride has a pH of 2.5 to 3.5. (Reynolds, 1996). Store in airtight containers and protect from light at a temperature not exceeding 25 degrees C (Reynolds, 1996).4. USES 4.1 Indications 4.1.1 Indications 4.1.2 Description 4.2 Therapeutic dosage 4.2.1 Adults 4.2.2 Children 4.3 Contraindications 5. ROUTES OF EXPOSURE 5.1 Oral 5.2 Inhalation 5.3 Dermal 5.4 Eye 5.5 Parenteral 5.6 Other 6. KINETICS 6.1 Absorption by route of exposure 6.2 Distribution by route of exposure 6.3 Biological half-life by route of exposure 6.4 Metabolism 6.5 Elimination and excretion 7. PHARMACOLOGY AND TOXICOLOGY 7.1 Mode of action 7.1.1 Toxicodynamics 7.1.2 Pharmacodynamics 7.2 Toxicity 7.2.1 Human data 126.96.36.199 Adults 18.104.22.168 Children 7.2.2 Relevant animal data 7.2.3 Relevant in vitro data 7.3 Carcinogenicity 7.4 Teratogenicity 7.5 Mutagenicity 7.6 Interactions 7.7 Main adverse effects 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS 8.1 Material sampling plan 8.1.1 Sampling and specimen collection 22.214.171.124 Toxicological analyses 188.8.131.52 Biomedical analyses 126.96.36.199 Arterial blood gas analysis 18.104.22.168 Haematological analyses 220.127.116.11 Other (unspecified) analyses 8.1.2 Storage of laboratory samples and specimens 22.214.171.124 Toxicological analyses 220.127.116.11 Biomedical analyses 126.96.36.199 Arterial blood gas analysis 18.104.22.168 Haematological analyses 220.127.116.11 Other (unspecified) analyses 8.1.3 Transport of laboratory samples and specimens 188.8.131.52 Toxicological analyses 184.108.40.206 Biomedical analyses 18.104.22.168 Arterial blood gas analysis 188.8.131.52 Haematological analyses 126.96.36.199 Other (unspecified) analyses 8.2 Toxicological Analyses and Their Interpretation 8.2.1 Tests on toxic ingredient(s) of material 18.104.22.168 Simple Qualitative Test(s) 188.8.131.52 Advanced Qualitative Confirmation Test(s) 126.96.36.199 Simple Quantitative Method(s) 18.104.22.168 Advanced Quantitative Method(s) 8.2.2 Tests for biological specimens 126.96.36.199 Simple Qualitative Test(s) 220.127.116.11 Advanced Qualitative Confirmation Test(s) 188.8.131.52 Simple Quantitative Method(s) 184.108.40.206 Advanced Quantitative Method(s) 184.108.40.206 Other Dedicated Method(s) 8.2.3 Interpretation of toxicological analyses 8.3 Biomedical investigations and their interpretation 8.3.1 Biochemical analysis 126.96.36.199 Blood, plasma or serum "Basic analyses"188.8.131.52 Urine "Dedicated analyses" "Optional analyses" "Basic analyses"220.127.116.11 Other fluids 8.3.2 Arterial blood gas analyses 8.3.3 Haematological analyses "Dedicated analyses" "Optional analyses" "Basic analyses" "Dedicated analyses" "Optional analyses"8.3.4 Interpretation of biomedical investigations 8.4 Other biomedical (diagnostic) investigations and their interpretation 8.5 Overall interpretation of all toxicological analyses and toxicological investigations Sample collection8.6 References 9. CLINICAL EFFECTS 9.1 Acute poisoning 9.1.1 Ingestion For toxicological analyses: whole blood 10 mL; urine 25 mL and gastric contents 25 mL. Biomedical analysis Blood gases, serum electrolytes, blood glucose and hepatic enzymes when necessary in severe cases. Toxicological analysis Qualitative testing for benzodiazepines is helpful to confirm their presence, but quantitative levels are not clinically useful. More advanced analyses are not necessary for the treatment of the poisoned patient due the lack of correlation between blood concentrations and clinical severity (Jatlow et al., 1979; MacCormick et al., 1985; Minder, 1989). TLC and EMIT: These provide data on the presence of benzodiazepines, their metabolites and possible associations with other drugs. GC or HPLC: These permit identification and quantification of the benzodiazepine which caused the poisoning and its metabolites in blood and urine. The onset of impairment of consciousness is relatively rapid in benzodiazepine poisoning. Onset is more rapid following larger doses and with agents of shorter duration of action. The most common and initial symptom is somnolence. This may progress to coma Grade I or Grade II (see below) following very large ingestions.9.1.2 Inhalation Reed Classification of Coma (Reed et al., 1952) Coma Grade I: Depressed level of consciousness, response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade II: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes and vital signs intact Coma Grade III: Depressed level of consciousness, no response to painful stimuli Deep tendon reflexes absent. Vital signs intact Coma Grade IV: Coma grade III plus respiratory and circulatory collapse Not relevant.9.1.3 Skin exposure No data.9.1.4 Eye contact No data.9.1.5 Parenteral exposure Overdose by the intravenous route results in symptoms similar to those associated with ingestion, but they appear immediately after the infusion, and the progression of central nervous system (CNS) depression is more rapid. Acute intentional poisoning by this route is uncommon and most cases are iatrogenic. Rapid intravenous infusion may cause hypotension, respiratory depression and apnoea.9.1.6 Other 9.2 Chronic poisoning 9.2.1 Ingestion Toxic effects associated with chronic exposure are secondary to the presence of the drug and metabolites and include depressed mental status, ataxia, vertigo, dizziness, fatigue, impaired motor co-ordination, confusion, disorientation and anterograde amnesia. Paradoxical effects of psychomotor excitation, delirium and aggressiveness also occur. These chronic effects are more common in the elderly, children and patients with renal or hepatic disease.9.2.2 Inhalation Administration of therapeutic doses of benzodiazepines for 6 weeks or longer can result in physical dependence, characterized by a withdrawal syndrome when the drug is discontinued. With larger doses, the physical dependence develops more rapidly. No data.9.2.3 Skin exposure No data.9.2.4 Eye contact No data.9.2.5 Parenteral exposure The chronic parenteral administration of benzodiazepines may produce thrombophlebitis and tissue irritation, in addition to the usual symptoms (Greenblat & Koch-Weser, 1973).9.2.6 Other No data.9.3 Course, prognosis, cause of death Benzodiazepines are relatively safe drugs even in overdose. The clinical course is determined by the progression of the neurological symptoms. Deep coma or other manifestations of severe central nervous system (CNS) depression are rare with benzodiazepines alone. Concomitant ingestion of other CNS depressants may result in a more severe CNS depression of longer duration.9.4 Systematic description of clinical effects 9.4.1 Cardiovascular The therapeutic index of the benzodiazepines is high and the mortality rate associated with poisoning due to benzodiazepines alone is very low. Complications in severe poisoning include respiratory depression and aspiration pneumonia. Death is due to respiratory arrest. Hypotension, bradycardia and tachycardia have been reported with overdose (Greenblatt et al., 1977; Meredith & Vale 1985). Hypotension is more frequent when benzodiazepines are ingested in association with other drugs (Hojer et al., 1989). Rapid intravenous injection is also associated with hypotension.9.4.2 Respiratory Respiratory depression may occur in benzodiazepine overdose and the severity depends on dose ingested, amount absorbed, type of benzodiazepine and co-ingestants. Respiratory depression requiring ventilatory support has occurred in benzodiazepine overdoses (Sullivan, 1989; Hojer et al.,1989). The dose-response for respiratory depression varies between individuals. Respiratory depression or respiratory arrest may rarely occur with therapeutic doses. Benzodiazepines may affect the control of ventilation during sleep and may worsen sleep apnoea or other sleep-related breathing disorders, especially in patients with chronic obstructive pulmonary disease or cardiac failure (Guilleminault, 1990).9.4.3 Neurological 22.214.171.124 Central nervous system (CNS) CNS depression is less marked than that produced by other CNS depressant agents (Meredith & Vale, 1985). Even in large overdoses, benzodiazepines usually produce only mild symptoms and this distinguishes them from other sedative-hypnotic agents. Sedation, somnolence, weakness, diplopia, dysarthria, ataxia and intellectual impairment are the most common neurological effects. The clinical effects of severe poisoning are sleepiness, ataxia and coma Grade I to Grade II (Reed). The presence of more severe coma suggests the possibility of co-ingested drugs. Certain of the newer short-acting benzodiazepines (temazepam, alprazolam and triazolam) have been associated with several fatalities and it is possible that they may have greater acute toxicity (Forrest et al., 1986). The elderly and very young children are more susceptible to the CNS depressant action of benzodiazepines.18.104.22.168 Peripheral nervous system 22.214.171.124 Autonomic nervous system 18.104.22.168 Skeletal and smooth muscle 9.4.4 Gastrointestinal The benzodiazepines may cause paradoxical CNS effects, including excitement, delirium and hallucinations. Triazolam has been reported to produce delirium, toxic psychosis, memory impairment and transient global amnesia (Shader & Dimascio, 1970; Bixler et al, 1991). Flurazepam has been associated with nightmares and hallucinations. There are a few reports of extrapyramidal symptoms and dyskinesias in patients taking benzodiazepines (Kaplan & Murkafsky, 1978; Sandyk, 1986). The muscle relaxation caused by benzodiazepines is of CNS origin and manifests as dysarthria, incoordination and difficulty standing and walking. Oral benzodiazepine poisoning will produce minimal effects on the gastrointestinal tract (GI) tract but can occasionally cause nausea or vomiting (Shader & Dimascio, 1970).9.4.5 Hepatic A case of cholestatic jaundice due focal hepatic necrosis was associated with the administration of diazepam (Tedesco & Mills, 1982).9.4.6 Urinary 220.127.116.11 Renal Vesical hypotonia and urinary retention has been reported in association with diazepam poisoning (Chadduck et al., 1973).18.104.22.168 Other 9.4.7 Endocrine and reproductive systems Galactorrhoea with normal serum prolactin concentrations has been noted in 4 women taking benzodiazepines (Kleinberg et al., 1977). Gynaecomastia has been reported in men taking high doses of diazepam (Moerck & Majelung, 1979). Raised serum concentrations of oestrodiol were observed in men taking diazepam 10 to 20 mg daily for 2 weeks (Arguelles & Rosner, 1975).9.4.8 Dermatological Bullae have been reported following overdose with nitrazepam and oxazepam (Ridley, 1971; Moshkowitz et al., 1990).9.4.9 Eye, ear, nose, throat: local effects Allergic skin reactions were attributed to diazepam at a rate of 0.4 per 1000 patients (Brigby, 1986). Brown opacification of the lens occurred in 2 patients who used diazepam for several years (Pau Braune, 1985).9.4.10 Haematological No data.9.4.11 Immunological Allergic reaction as above (see 9.4.8).9.4.12 Metabolic 126.96.36.199 Acid-base disturbances No direct disturbances have been described.22.214.171.124 Fluid and electrolyte disturbances No direct disturbances have been described.126.96.36.199 Others 9.4.13 Allergic reactions Hypersensitivity reactions including anaphylaxis are very rare (Brigby, 1986). Reactions have been attributed to the vehicle used for some parenteral diazepam formulations (Huttel et al., 1980). There is also a report of a type I hypersensitivity reaction to a lipid emulsion of diazepam (Deardon, 1987).9.4.14 Other clinical effects Hypothermia was reported in 15% of cases in one series. (Martin, 1985; Hojer et al., 1989).9.4.15 Special risks Pregnancy9.5 Other Passage of benzodiazepines across the placenta depends on the degree of protein binding in mother and fetus, which is influenced by factors such as stage of pregnancy and plasma concentrations of free fatty acids in mother and fetus (Lee et al., 1982). Adverse effects may persist in the neonate for several days after birth because of immature drug metabolising enzymes. Competition between diazepam and bilirubin for protein binding sites could result in hyperbilirubinemia in the neonate (Notarianni, 1990). The abuse of benzodiazepines by pregnant women can cause withdrawal syndrome in the neonate. The administration of benzodiazepines during childbirth can produce hypotonia, hyporeflexia, hypothermia and respiratory depression in the newborn. Benzodiazepines have been used in pregnant patients and early reports associated diazepam and chlordiazepoxide with some fetal malformations, but these were not supported by later studies (Laegreid et al., 1987; McElhatton, 1994). Breast feeding Benzodiazepines are excreted in breast milk in significant amounts and may result in lethargy and poor feeding in neonates. Benzodiazepines should be avoided in nursing mothers (Brodie, 1981; Reynolds, 1996). Dependence and withdrawal9.6 Summary 10. MANAGEMENT 10.1 General principles Benzodiazepines have a significant potential for abuse and can cause physical and psychological dependence. Abrupt cessation after prolonged use causes a withdrawal syndrome (Ashton, 1989). The mechanism of dependence is probably related to functional deficiency of GABA activity. Withdrawal symptoms include anxiety, insomnia, headache, dizziness, tinnitus, anorexia, vomiting, nausea, tremor, weakness, perspiration, irritability, hypersensitivity to visual and auditory stimuli, palpitations, tachycardia and postural hypotension. In severe and rare cases of withdrawal from high doses, patients may develop affective disorders or motor dysfunction: seizures, psychosis, agitation, confusion, and hallucinations (Einarson, 1981; Hindmarch et al, 1990; Reynolds, 1996). The time of onset of the withdrawal syndrome depends on the half-life of the drug and its active metabolites; the symptoms occur earlier and may be more severe with short -acting benzodiazepines. Others risk factors for withdrawal syndrome include prolonged use of the drug, higher dosage and abrupt cessation of the drug. Abuse Benzodiazepines, particularly temazepam, have been abused both orally and intravenously (Stark et al., 1987; Woods, 1987; Funderburk et al, 1988) Criminal uses The amnesic effects of benzodiazepines have been used for criminal purposes with medicolegal consequences (Ferner, 1996). Most benzodiazepine poisonings require only clinical observation and supportive care. It should be remembered that benzodiazepine ingestions by adults commonly include other drugs and other CNS depressants. Activated charcoal normally provides adequate gastrointestinal decontamination. Gastric lavage is not routinely indicated. Emesis is contraindicated. The use of flumazenil is reserved for cases with severe respiratory or cardiovascular complications and should not replace the basic management of the airway and respiration. Renal and extracorporeal elimination methods are not effective.10.2 Life supportive procedures and symptomatic/specific treatment The patient should be evaluated to determine adequacy of airway, breathing and circulation. Continue clinical observation until evidence of toxicity has resolved. Intravenous access should be available for administration of fluid. Endotracheal intubation, assisted ventilation and supplemental oxygen may be required on rare occasions, more commonly when benzodiazepines are ingested in large amounts or with other CNS depressants.10.3 Decontamination Gastric lavage is not routinely indicated following benzodiazepine overdose. Emesis is contraindicated because of the potential for CNS depression. Activated charcoal can be given orally.10.4 Enhanced elimination Methods of enhancing elimination are not indicated.10.5 Antidote treatment 10.5.1 Adults Flumazenil, a specific benzodiazepine antagonist at central GABA-ergic receptors is available. Although it effectively reverses the CNS effects of benzodiazepine overdose, its use in clinical practice is rarely indicated.10.5.2 Children Use of Flumazenil is specifically contraindicated when there is history of co-ingestion of tricyclic antidepressants or other drugs capable of producing seizures (including aminophylline and cocaine), benzodiazepine dependence, or in patients taking benzodiazepines as an anticonvulsant agent. In such situations, administration of Flumazenil may precipitate seizures (Lopez, 1990; Mordel et al., 1992). Adverse effects associated with Flumazenil include hypertension, tachycardia, anxiety, nausea, vomiting and benzodiazepine withdrawal syndrome. The initial intravenous dose of 0.3 to 1.0 mg may be followed by further doses if necessary. The absence of clinical response to 2 mg of flumazenil within 5 to 10 minutes indicates that benzodiazepine poisoning is not the major cause of CNS depression or coma. The patient regains consciousness within 15 to 30 seconds after injection of flumazenil, but since it is metabolised more rapidly than the benzodiazepines, recurrence of toxicity and CNS depression can occur and the patient should be carefully monitored after initial response to flumazenil therapy. If toxicity recurs, further bolus doses may be administered or an infusion commenced at a dose of 0.3 to 1.0 mg/hour (Meredith et al., 1993). The initial intravenous dose of 0.1 mg should be repeated each minute until the child is awake. Continuous intravenous infusion should be administered at a rate of 0.1 to 0.2 mg/hour (Meredith et al., 1993).10.6 Management discussion Most benzodiazepine poisonings require only clinical observation and supportive care. Flumazenil is the specific antagonist of the effects of benzodiazepines, but the routine use for the treatment of benzodiazepine overdosage is not recommended. The use of Flumazenil should only be considered where severe CNS depression is observed. This situation rarely occurs, except in cases of mixed ingestion. The administration of flumazenil may improve respiratory and cardiovascular function enough to decrease the need for intubation and mechanical ventilation, but should never replace basic management principles.11. ILLUSTRATIVE CASES 11.1 Case reports from literature 12. Additional information 12.1 Specific preventive measures 12.2 Other 13. REFERENCES Flumazenil is an imidazobenzodiazepine and has been shown to reverse the sedative, anti-convulsant and muscle-relaxant effects of benzodiazepines. In controlled clinical trials, flumazenil significantly antagonizes benzodiazepine-induced coma arising from anaesthesia or acute overdose. However, the use of flumazenil has not been shown to reduce mortality or sequelae in such cases. The administration of flumazenil is more effective in reversing the effects of benzodiazepines when they are the only drugs producing CNS toxicity. Flumazenil does not reverse the CNS depressant effects of non-benzodiazepine drugs, including alcohol. The diagnostic use of flumazenil in patients presenting with coma of unknown origin can be justified by its high therapeutic index and the fact that this may limit the use of other diagnostic procedures (CT scan, lumbar puncture, etc). Flumazenil is a relatively expensive drug and this may also influence its use, especially in areas with limited resources. Arguelles AE, & Rosner J. (1975) Diazepam and plasma testosterone levels. Lancet, ii: 607.14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES) Ashton CH (1989) Drug-induced stupor and coma: some physical signs and their pharmacological basis. Adverse drug React Acute Poisoning Rev, 8: 1-59. Bixler EO, Kales A, Manfredi RL, Vgontzas AN, Tyson KL, & Kales JD (1991) Next-day memory impairment with triazolam use. Lancet, 337: 827-831. Brigby M. (1986) Drug induced cutaneous reactions. JAMA, 256: 3358-63. Brodie RR, Chasseaud LF & Taylor T (1981) Concentrations of N- descyclopropylmethyl-prazepam in whole-blood, plasma and milk after administration of prazepam to humans. Biopharm Drug Dispos, 2: 59-68. Chadduck WM, Loar CR & Denton IC. (1973) Vesical hypotonicity with diazepam. J Urol, 109: 1005-1007. Deardon DJ. (1987) Acute hypersensivity to IV Diazulmuls. Br J Anaesth, 59: 391. Einarson TR (1981) Oxazepam withdrawal convulsions. Drug Intell Clin Pharm, 15: 487. Ellenhorn, M. (1996) Medical Toxicology. 2nd Ed., Elsevier. Ferner RE (1996) Forensic Pharmacology, 1st Ed. Oxford University Press, Oxford. Forrest ARW, Marsh I, Bradshaw C & Braich SK (1986) Fatal temazepam overdoses (letter). Lancet, 2: 226. Funderburk FR, Griffiths RR, McLeod DR, Bigelow GE, Mackenzie A, Liebson IA & Newmeth-Coslett R (1988) Relative abuse liability of lorazepam and diazepam: an evaluation in "recreational" drug users. Drug Alcohol Depend, 22: 215-222. Greenblatt DJ, Allen MD, Noel BJ et al (1977) Acute overdose with benzodiazepine derivatives. Clin Pharm Ther, 21: 497-513. Guilleminault C. (1990) Benzodiazepines, bresthing and sleep. Am J Med, 88 (suppl 3A): 25S - 28S. Hindmarch I, Beaumont G, Brandon S, & Leonard, B. (1990) Benzodiazepines Current Concepts, John Wiley & Sons Ltd, UK. Hojer J, Baehrendtz S & Gustafsson L. (1989) Benzodiazepine poisoning: experience of 702 admissions to an intensive care unit during a 14-year period. J Intern Med, 226: 117-122. Huttel MS, Schou Olesen A & Stofferson E (1980) Complement- mediated reactions to diazepam with Cremophor as solvent. Br J Anaesth, 52: 77-9. Hyams SW & Keroub C (1977) Glaucoma due to diazepam. Am J Psychiatry, 134: 477-479. Kaplan SR, & Murkofsky C (1978) Oral-buccal dyskinesic synptoms associated with low dose benzodiazepine treatment. Am J Psychiatry, 135: 1558-1559. Kleinberg DL, Noel GL & Frantz AG (1977) Galactorrhea a study of 235 cases. N Eng J Med 296: 589-600. Laegreid L, Olegard R, & Wahlstrom J (1987) Abnormalities in children exposed to benzodiazepines in utero. Lancet, 1:108- 109. Lee JN, Chen SS, Richens A, Menabawey m & Chard T (1982) Serum protein binding of diazepam in maternal and foetal serum during pregnancy. Br J Clin Pharmacol, 14: 551-4. Lopez A & Rebollo J (1990) Benzodiazepine withdrawal syndrome after a benzodiazepine antagonist. Crit Care Med, 18:1480- 1481. Martin SM (1985) The effect of diazepam on body temperature change in humans during cold exposure. J Clin Pharmacol, 25: 611- 613. McCormick SR, Nielsen J & Jatlow PI (1985) Alprazolam overdose: clinical findings and serum concentrations in two cases. J Clin Psychiatr, 46:247-248. McElhatton PR. (1994) The effects of benzodiazepines use during pregnancy and lactation. Reprod Toxicol, 8: 461-75. Meredith TJ, Jacobsen D, Haines JA, Berger JC (1993) IPCS/CEC Evaluation of Antidotes Series, Vol1, Naloxone, flumazenil and dantrolene as antidotes, 1st ed. Cambridge University Press, Cambridge. Meredith TJ, & Vale JA (1985) Poisoning due to psychotropic agents. Adverse Drug React Acute Poison Rev, 4: 83-122. Minder EI (1989) Toxicity in a case of acute and massive overdose of chlordiazepoxide and its correlation to blood concentration. Clin Toxicol, 27: 117-127. Moerck HJ, Majelung G (1979) Gynaecomastia and diazepam abuse.Lancet, i: 1344-5. Mordel A, Winkler E, Almog S, Tirosh M & Ezra D (1992) Seizures after flumazenil administration in a case of combined benzodiazepine and tricyclic antidepressant overdose. Crit Care Med, 12: 1733-1734. Notarianni LJ. (1990) Plasma protein binding of drugs in pregnancy and neonates. Clin Pharnacokinet, 18: 20-36. Pau Braune H (1985) [Eyes effect of diazepam.] Klin Monatsbl Augenheilkd, 187: 219-20 (in German). Reed C E, Driggs M F, & Foote CC (1952) Acute barbiturate intoxication. A study of 300 cases based on a physiologic system of classification of the severity of intoxication. Ann Intern Med, 37: 390-396. Reynolds J (1996) Martindale, The Extra Pharmacopeia. 30th ed. The Pharmaceutical Press, London, 699-744. Ridley CM (1971) Bullous lesions in nitrazepan overdosage. Br Med J, 3: 28-29. Sandyk R (1986) Orofacial diskynesias associated with lorazepam therapy. Clin Pharm, 5: 419-21. Shader RI & Dimascio A (1970) Psychotropic drug side effects, 1st ed. Willians & Wilkins, Baltimore. Stark C, Sykes R & Mullin P (1987) Temazepam abuse (letter). Lancet, 2:802-803. Sullivan RJ Jr (1989) Respiratory depression requiring ventilatory support following 0.5 mg of Triazolam. J Am Geriatr, Soc 37: 450-452. Tedesco FJ, & Mills LR. (1982) Diazepam hepatites. Dig Dis Sci 27: 470-2. Author: Dr Ligia Fruchtengarten Poison Control Centre of Sao Paulo - Brazil Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 FAX / Phone: 55 11 2755311 E-mail: firstname.lastname@example.com Mailing Address: Hospital Municipal Dr Arthur Ribeiro de Saboya - Coperpas 12 Centro de Controle de Intoxicaçoes de Sao Paulo Av Francisco de Paula Quintanilha Ribeiro, 860 04330 - 020 Sao Paulo - SP - Brazil. Date: July 1997 Peer Review: INTOX 10 Meeting, Rio de Janeiro, Brazil, September 1997. R. Ferner, L. Murray (Chairperson), M-O. Rambourg, A. Nantel, N. Ben Salah, M. Mathieu- Nolf, A.Borges. Review 1998: Lindsay Murray Queen Elizabeth II Medical Centre Perth, Western Australia. Editor: Dr M.Ruse, April 1998
See Also: Toxicological Abbreviations


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1. The problems we are trying to solve
2. Mission and Vision for the Global Diaspora Associations of Norway
3. Objectives for the International Diaspora of Norway
4. What can you do to start solving your problem on this platform today?
1. The problems we are trying to solve
Several people from Norway are leaving their home country to go to others countries each year, seeking better opportunities, or trying to adjust to life's challenges and solicitations. Sometimes, brain drain (migration of educated people) is seen as one of the greatest threats against the development of most countries including Norway. Nevertheless, some developed countries are promoting policies and immigration laws that encourage foreign educated pundits or talented graduate students to leave Norway to move abroad.
Unfortunately, many Norwegians are usually disappointed by what they see after moving abroad, and others are disconnected from people and opportunities in Norway as well as in their new host country. Because of a lack of information or right connections, those who migrate do not always produce the best of themselves or successfully integrate into their new environment. The immigrants from Norway who succeed often don't collaborate or network with the newly arriving immigrants or with those who are not reaching their dreams.
At the same time, Norway would love to find and engage with the Norwegians living in the diaspora, but this type of relationship is not working well. Besides money they send back to their relatives, the global Diaspora of Norway do not contribute to the development of Norway as wished. Those who want to engage in humanitarian, fundraising, or philanthropy activities to give back don't know how, where, and whom to contact to reach the real needy or to solve the real problems. At the same time, the diasporas of Norway are usually unknown by many businesses, nonprofits and other organizations with whom they can do business in their country of residence and in Norway. This global problem impoverishes nations and deprives many organizations from reaching most of their potential market, clients, and customers.
With the increasing rise of crises, wars, and catastrophic events around the globe, migration of the people of Norway will keep growing and its corresponding problems will get worse if appropriate actions are not taken now. To sustainably solve this problem, a global system must be built where the diaspora associations of Norway, the people and organizations in Norway and in the host country of the diaspora can work together to help each other mutually. That's what we are trying to achieve here via the DiasporaEngager platform!
- Are you from Norway or are you trying to find opportunities from Norwegians living in the diaspora or living in Norway?
- Are you trying to find and engage with the Norwegians?
- Are you looking for a diaspora association of Norway?
- Are you seeking business opportunities or something else from the diaspora network of Norway?
- Do you have a message or something to share with the Norwegian diasporas?
- Are you an authority from Norway trying to reach out to the Norwegians living in the diaspora?
If you said yes to anything above, we can help you. Please keep reading to see how.
2. Mission and Vision for the Global Diaspora Associations of Norway
DiasporaEngager aims at being the world's premier provider of liaisons between all diasporas, including the global diaspora of Norway, the people and organizations living in Norway, as well as the people and organizations in the host country of the Norwegian diasporas, to detect, harvest, and transfer resources, services, and opportunities between people and their nations in a win-win framework. DiasporaEngager is the global diaspora engagement platform that aims at connecting the international diasporas of Norway to each other and to the diaspora associations of other countries, and to opportunities with governments, nonprofits, businesses, laboratories, international institutions, schools, and research institutions in Norway and abroad. DiasporaEngager platform assists the global diasporas of Norway and the organizations in their networks to provide effective working, networking, and development strategies in Norway as well as in the current country of residence of the Norwegian diaspora.
DiasporaEngager aims at creating and linking all the diaspora networks of Norway with their corresponding immigrants, and with people and organizations; then, uses this international network as a tool to:
- Mobilize resources and maximize the outcome of networking and cooperation in any area pertaining to the development of Norway, the Norwegians, and the nations and organizations involved in this effort;
- Create an international social media platform based on the potential of the global diaspora of Norway and use that as a strong resource for education, communication, consulting, lobbying, diplomacy, advocacy, benchmarking, capacity building, entrepreneurship, fundraising, investment, business opportunities, and much more, to sustainably improve lives and the development of nations, including Norway, based on the networks of the professionals of Norway living abroad and at home.
In order words, we aim at being the developmental social media platform that goes beyond just friendship and networking, by creating an advanced pipeline where living in the diaspora can network and interact:
(a) among themselves according to their country of residence and/or their interest;
(b) with their fellow citizens living back home in Norway;
(c) with the people and organizations in their host countries or current country of residence, and
(d) with people the diaspora associations of other countries in order to harness, exchange, and transfer opportunities to bridge developmental gaps between the Norwegians abroad or at home, and other nations according to their needs and means in a win-win framework.
All it takes to start using this global platform of the diaspora network of Norway is to register a free account. If you have not registered an account on DiasporaEngager yet, please click here to register today: https://diasporaengager.com/miniRegister. It is free!
3. Objectives for the International Diaspora of Norway
As far as the diaspora association of are concerned, the goal of DiasporaEngager is to create a global online setting that will allow the people of living in the diaspora to develop themselves in order to be able to develop their country of origin and of residence. As an example,
- We build a global Norwegian Diaspora Directory and a skills database of the citizens of Norway living in the diaspora and we encourage them to list and make themselves more searchable and accessible to those from their host country and from their home country and vice versa.
- We help Norway to better know who and where its diasporas are, in addition to knowing more about the foreigners and diaspora associations living in Norway.
- We encourage all the global diaspora of Norway to network among each other and to collaborate with Norway to assist in alleviating the negative impact of brain drain.
- We restore the connection, improve communication and the working relationships among the members of the diaspora of Norway, their country of birth (i.e. Norway) and their current country of residence.
- We offer the Norwegian diaspora network a diverse range of services to better organize themselves and help each other abroad.
- We facilitate the creation of professional networks among the diasporas of Norway (e.g. Norway Doctorates living in the diaspora, Norway scientists in the diaspora, Norway Nurses in the diaspora, etc.).
- We inform the diasporas of Norway about existing opportunities in their host country as well as in their native countries and vice versa.
- We encourage the Norwegians living abroad to invest their time and energy in the development of Norway.
- We allow the countries that are hosting the diaspora of Norway to better understand the potential and opportunities of the Norwegian diaspora.
- We serve as a channel between the Norwegian diaspora associations and their country of birth to harness as well as to transfer any opportunities and resources toward the places of need.
- We assist the Norwegians to quickly explore, discover, and invest in new opportunities around the globe.
- We provide the international diasporas of Norway with the tools to influence the decision making in Norway while being more efficient and productive in their host countries.
- We ease the integration of new immigrants from Norway into the new host country.
- We allow the diaspora network of Norway to better enlighten the leaders and institutions in Norway with new technologies and cutting edge sciences.
- We help the government of Norway and Norwegian global diaspora to create and understand their path to success in a mutual way.
- We also aim at working with and encouraging the institutions and government of Norway to use this platform to find and engage with their diaspora wherever they are living.
- And much more. To learn about other services that we provide, please click here: https://diasporaengager.com/extPage/InterestAreas.
4. What can you do to start using this platform today?
All it takes to start using this global platform is to register a free account. If you have not registered an account on DiasporaEngager yet, please click here to register today: https://diasporaengager.com/miniRegister. It is free!
- After registering, you will go to your homepage where you will post your needs and/or offers so others can find them and help you, or you can help meet someone else's need.
- You can search and view needs and offers posted by others that relate to your areas of interest.
- You can search for individuals or organizations interested in similar things like you.
- You can directly contact people or organizations you are interested in for networking, assistance, or any other needs or offers of your choice.
- You can get involved in activities that members of your areas of interest are doing or you can join or create forums related to your areas of interest.
- From your homepage, you can create a new group (e.g. diaspora group of Norway living in any country or sharing a specific interest) to discuss and collaborate with others that share the same interest.
- You can also partner or collaborate with us.
- And a whole lot more.
If you are not a DiasporaEngager User yet, please click here to register today or go to: http://diasporaengager.com/miniRegister. It is totally free.
To start receiving updates and opportunities related to the global diaspora and/or to the diaspora of Norway, please click here to subscribe to our newsletter today or go to http://diasporaengager.com/Newsletter! It is free!
To learn about other services that we provide, please click here: https://diasporaengager.com/extPage/InterestAreas.
For any questions or suggestions, please contact us at http://DiasporaEngager.com/contact.
If you belong to a diaspora association, please help us contact the leaders of that association so that they sign up themselves and your diaspora association on this global platform. It is better to partner with other diasporas globally than work alone in isolation. Please help us to spread the word about this global diaspora engagement platform.
We look forward to seeing you on www.DiasporaEngager.com and hope we can help meet your needs!
Thank you.


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You can check your current Pennsylvania EBT card balance using different methods including calling the EBT balance phone number, checking EBT balance online and by looking at your grocery receipt. Your Pennsylvania Access card can be used at any store location that accepts food stamps, including outside the state. The department that handles the SNAP program in your state is the Pennsylvania Department of Public Welfare. Below we provide information on the different ways you can check your Pennsylvania EBT card balance. Make sure you have your card and pin number ready.
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The move, which has no bearing on his chances of winning office, follows the imposition of US sanctions on Lee and other Hong Kong and Chinese officials in 2020
YouTube | Hong Kong | Facebook
Last Updated at April 20, 2022 23:37 IST
(This story has not been edited by Business Standard staff and is auto-generated from a syndicated feed.)
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Understanding International Relations Theory
The course aims to introduce the key assumptions of the international relations theory as a part of social science and as an analytic tool, focusing on the problems of war and peace, foreign policy decision-making, etc. The course combines historic approach and analysis of the modern political problems. The historic part shows the evolution of the international relations theory from being a part of political philosophy to its emergence as a special branch of political science, which is essential to understand the key ideas of the IR science. The lectures also include broad outline of the modern concepts and debates in the context of the contemporary political problems, such as rise of China and other emerging powers, threat of terrorism, US-Russia confrontation, etc.
The lectures of the two outstanding Russian scholars and political analysts – Timofey Bordachev and Dmitry Suslov - cover such fields as the problems of international security and conflict resolution, international economic relations, foreign policy decision-making, global governance, the role of power in the IR.


text: Post approved by David Crane for information purposes only. DefRev does not endorse any of the products described in this story: "Just issued, Ebook on the Colt pistols. Its title : Colt 1903 "Hammerless" by Gérard Henrotin Many ebooks on various firearms are now available in our site. Find them all at… the url : http://users.skynet.be/HL-Editions/ebook/liste01.htm Downloading page of the …Read More »


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The ThetaHealing® Manifesting and Abundance Seminar has the following criteria taught by a certified ThetaHealing® Instructor:
Manifesting Downloads in a Theta State
How blocks on abundance are seldom about money.
Exercises to remove your blocks
Exercise: Divine Timing
Exercise: Remembering your Future
Exercise: I am stuck exercise.
Exercise: How to create your future from the Seventh Plane and manifesting in the highest and the best way
Exercise: Bless your money
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*For the student that is already a Basic and Advanced ThetaHealing® Instructor, upon completion of this seminar you may apply with the ThetaHealing® Institute of Knowledge to teach this seminar.
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In ThetaHealing®, the concept of manifesting is the Belief that it is possible to create something into the physical using the connection to the Creator of All That Is. Every statement, thought and action is reflected by what we are manifesting in our lives.
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ThetaHealing® Basis DNA
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2 days
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text: bio-night2 March 09, 2017 Alicia Stella Author: Alicia Stella Category: Tags: Alicia Stella Alicia has been visiting theme parks since the age of 3, has a knack for memorizing park maps, loves theme park renovations and cannot wait to ride something new. She can often be found wandering the parks and riding coasters! 0 Comments Leave a CommentCancel reply


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454 - Five Forces Analysis
Last Updated by wbot | Update This Page Now
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Cindy Carlson
Real Estate Agent at
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Get introduced
By clicking "Submit", I consent to HomeLight's Terms of Service and Privacy Policy, and I consent to have HomeLight or one of its partners to contact me via autodialed phone calls and text messages, and prerecorded messages, on the landline or cell number I provided even if I'm on any Do-Not-Call list and even if I am charged for the call or text. I understand that my consenting is not a condition of my receiving HomeLight's services, and that I can call 866-627-3398 for services if I do not consent.
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More about Cindy Carlson
I am involved in my community, on the school board of the Silver Valley Christian Academy, a member of the Silver Valley Chamber of Commerce and Historic Wallace Chamber of Commerce, Ladies Golf Club Member & Sports Committee and a member of Kiwanis. I moved to the Silver Valley in 1974. I am married and have a son, daughter-in-law and 4 grandchildren in the area. I like to spend my free time with family and friends camping, golfing, bike riding and skiing.
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from the United States Court of Appeals for the Fifth Circuit
See other cases from the Fifth Circuit.
Petition DENIED.
Waiver of right of respondent United States to respond filed.
Petition for a writ of certiorari and motion for leave to proceed in forma pauperis filed. (Response due November 24, 2023)
Benancio Castaneda, Petitioner, represented by Brian Daniel Poe
United States, Respondent, represented by Elizabeth B. Prelogar


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Tiffany Lakes Kendall
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For this hot date, I'm down to meet you at a bar. If you feel like it, I wouldn't mind setting up a meeting in the woods. To make me come during this hookup, I'm looking for a man with a huge thick cock. Otherwise, I'm very cool if you make me climb the curtains and I have no taboo. I love showing myself naked in the forest and having my picture taken. However, what really turns me on are reports in atypical places (parking lots, toilets, etc.), it's up to you to be innovative in the streets of Lakes. So, I invite you to contact me now if you want to fuck me. I want a dirty man. See you soon.
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