Barbiturate Poisoning Research Articles

Florbela Espanca: The Limbs of a Passion

WV th the advent of the Flower Revolution in Portugal in 1974 and the subsequent reevaluation of twentieth-century women writers, Florbela Espanca (1894-1930) emerges as the first in a long line of feminist protest voices. When she died in Matosinhos near Oporto from an overdose of barbiturates on December 7, 1930, the eve of her thirty-sixth birthday, Bela was relatively unknown in Portuguese literary circles except for a small coterie of friends and admirers including her Italian translator and confidant Professor Guido Battelli and the poet Americo Durao, the latter who dubbed her Soror Saudade. The combination of an unconventional lifestyle, three husbands, and an uncommon drive to compete in an Iberian macho world of sexual prowess and sentiments scandalized her fellow townspeople of Vila Vigosa, and greatly contributed to her detractors dismissing her and her poetry as the prattle of a neurasthenic, the derrocada louca of her

Respiratory Muscle Fatigue and Ventilatory Failure

The respiratory system consists of two parts: the lung (the gas-exchanging organ) and the ventilatory pump that ventilates the lung. Failure of the lung leads mainly to hypoxemia. Failure of the pump leads mainly to alveolar hypoventilation, which in turn leads to hypercapnia1 (Fig 1). The failure of the pump theoretically may occur at any site from the central nervous system (CNS) to the contractile machinery. For practical purposes there are 3 major causes of pump failure: (1) The output of the CNS may primarily be inadequate—for example, after barbiturate intoxication; or the pattern of breathing is not optimal (for example, during an unsuccessful weaning period with the patient breathing with small tidal volume, resulting in an increase in VD/VT).

Effect of oxiracetam on cerebral cholinergic imbalance secondary to an nmda-receptor blockade

Nearly three decades have now passed since the discovery of the piracetam-like nootropics, compounds which exhibit cognition-enhancing properties, but for which no commonly accepted mechanism of action has been established. This review covers clinical, pharmacokinetic, biochemical and behavioural results presented in the literature from 1965 through 1992 (407 references) of piracetam, oxiracetam, pramiracetam, etiracetam, nefiracetam, aniracetam and rolziracetam and their structural analogues. The piracetam-like nootropics are capable of achieving reversal of amnesia induced by e.g., scopolamine, electrocon-vulsive shock and hypoxia. Protection against barbiturate intoxication is observed and some benefit in clinical studies with patients suffering from mild to moderate degrees of dementia has been demonstrated. No affinity for the α1-, α2-, β-, muscarinic, 5-hydroxytryptamine-, dopamine, adenosine-A1, μ-opiate, γ-aminobutyric acid (GABA) (except for nefiracetam (GABAA)), benzodiazepine and glutamate receptors has been found. The racetams possess a very low toxicity and lack serious side effects. Increased turnover of different neurotransmitters has been observed as well as other biochemical findings e.g., inhibition of enzymes such as prolylendopeptidase. So far, no generally accepted mechanism of action has, however, emerged. We believe that the effect of the racetams is due to a potentiation of already present neurotransmission and that much evidence points in the direction of a modulated ion flux by e.g., potentiated calcium influx through non-l-type voltage-dependent calcium channels, potentiated sodium influx through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor gated channels or voltage-dependent channels or decreases in potassium efflux. Effects on carrier mediated ion transport are also possible.

The Origins of Canine Serum Amylases and Lipase

In human beings, isoamylase analysis is useful in determining the tissue source accounting for hyperamylasemia and in the diagnosis of exocrine pancreatic insufficiency (EPI).4,9 In dogs, serum isoamylase analysis is more sensitive than total serum amylase activity in detecting pancreatiti~.~ Serum isoamylase analysis by agarose gel electrophoresis is not helpful in the diagnosis of canine EPI, contrary to preliminary findings using cellulose acetate electrophoresis.2 Some of the lack of sensitivity of isoamylase analysis for canine EPI may be due to extrapancreatic production of the purported pancreatic-specific isoamylase-3.2,8 The pancreas has the greatest activity of specific amylase followed by the duodenal mucosa that has about 1 .O% of pancreatic activity. The specific amylase activity of 14 other tissues was less than 0.05% of the pancreatic activity.* All canine tissues studied have isoamylase-4 activity. About half of the pancreatic activity and about 13% of the duodenal mucosal activity are in the isoamylase-3 fraction. No other tissues show isoamylase-3 activity with the agarose gel electrophoretic technique. The small intestine, therefore, may be a source of a small amount of serum isoamylase-3 activity. Alternatively, duodenal isoamylase-3 activity may be a contaminant from exposure to pancreatic juice. Lipase activity is also found in the pancreas and duodenum.6 The contributions of these tissue sources to serum activity are not known. To study the origins of serum amylases and lipase activities in the dog, pancreatic and duodenal arteriovenous differences were determined. Amylases were measured in short-term in vitro incubations of pancreatic acini and duodenal mucosal cells to determine if both tissues contain isoamylase-3 activity. Pancreatic and small intestinal arterial and venous blood samples were obtained from eight adult dogs from which food had been withheld for 12 hours. Pancreata and duodenums were collected from six adult dogs immediately following death by barbiturate overdose. The blood samples were allowed to clot at room temperature, and the serum was collected by centrifugation. Samples were stored frozen at -20 C until analyzed for amylase, lipase, and isoamylase

Improved brain metabolism with fructose 1-6 diphosphate during insulin-induced hypoglycemic coma

The effect of fructose 1-6 diphosphate (FDP) on brain metabolism and brain function was investigated in hypoglycemic rabbits. The electroencephalogram and differences in oxygen content of arterial and cerebral venous blood were used as indicators for brain metabolic activity. Hypoglycemic coma was induced and maintained for 1 hour by insulin administration. At the onset of isoelectric EEG, six rabbits were treated with FDP and five rabbits received 0.9% saline. The animals were killed by an overdose of barbiturate 60 minutes after hypoglycemic recovery with glucose. FDP-treated rabbits had lower arterial glucose concentration after 40 minutes of treatment (p less than .05) and a significantly greater difference between the oxygen content of arterial and venous blood after 40 minutes (p less than .01), and after 60 minutes (p less than .025) of FDP infusion than saline-treated rabbits. FDP-treated rabbits also had a lower cerebral glucose-oxygen index than did saline-treated rabbits (p less than .005, after 20 and 40 minutes of FDP infusion). FDP administration was followed by a return of EEG activity during hypoglycemia, whereas saline produced no such effect. After glucose infusion, EEG activity was improved in FDP-treated rabbits; in saline-treated rabbits, minimal or no EEG activity was observed. The data suggest the possibility that, at the doses given in this study, FDP is taken up and used as a metabolic substrate by the brain.

Not Always on the Level

This is an autobiography of a British medical graduate who develops a manic-depressive illness. The author is the son of a north country general medical practitioner; he attended medical school in London, ultimately specializing in internal medicine (and taking an academic appointment in Canada). The idiom and terminology of most of the book are quite British, and, because of the differences in medical education, parts of the book will appear somewhat strange to the North American reader. It is quite authentic, however, and clearly reveals the trials, tribulations, and rewards of a physician struggling to make his way in post-World War II Britain. His descriptions of tuberculous meningitis in children and the use of picrotoxin in barbiturate poisoning are examples of this earlier medical era. Much of the book concerns the author's training and experiences, punctuated liberally with his views on various medical topics such as intensive care units. Only

Short latency somatosensory evoked potentials and brain-stem auditory evoked potentials in coma due to CNS depressant drug poisoning. Preliminary observations

In patients in coma due to severe CNS depressant drug overdose the central somatosensory conduction time (CCT) after median nerve stimulation is prolonged and N20 is dispersed. Brain-stem auditory evoked potentials demonstrate delayed interpeak latencies (IPLs) I–III, III–V and I–V. This was observed in 4 out of 5 patients investigated after intake of an overdose of amitriptyline (2 cases), barbiturates, meprobamate and nitrazepam (one case each). Toxic levels of drug overdose were related to prolonged CCT and IPLs, whereas normal CCT and IPLs were found at therapeutic drug plasma levels. CCT, IPLs and dispersion of N20 decreased during the course of coma. All patients were successfully treated. It appeared that SSEP and BAEP investigations could make a distinction between a ‘toxic’ and a ‘therapeutic’ coma level in severe drug overdose. It further appeared that normalization of CCT and IPLs preceded clinical improvement.

Barbiturate poisoning and gastrointestinal propulsion.

Anaesthetic doses of pentobarbitone (50 mg/kg) were found to inhibit gastric emptying and gastrointestinal transit in the rat. Gastric emptying was more profoundly suppressed than gastrointestinal transit. Phenobarbitone (150 mg/kg) had a similar effect. Since pentobarbitone and phenobarbitone also blocked the peristaltic reflex in the isolated small intestine of the guinea-pig, it would appear that the inhibitory effect of anaesthetic doses of barbiturates on gastrointestinal motility is mainly due to a direct action on the digestive tract. Together with the observation that considerable amounts of phenobarbitone were found in the stomach of an intoxicated patient 3 days after drug intake, these results might indicate that gastric lavage should also be considered in the treatment of protracted barbiturate poisoning.

Protection against the lethal effects of pentobarbital in mice by a benzodiazepine receptor inverse agonist, 6,7-dimethoxy-4-ethyl-3-carbomethoxy-beta-carboline.

The benzodiazepine receptor inverse agonist 6,7-dimethoxy-4-ethyl-3-carbomethoxy-beta-carboline (DMCM) (1.5-15 mg/kg) was administered to mice 5 min after a lethal (LD94) injection of pentobarbital. DMCM (1.5-5 mg/kg) increased short-term (1 h) survival in a dose-dependent fashion, with an optimum survival rate more than five times greater than mice receiving pentobarbital alone. Statistically significant increases in long-term (24 h) survival were also observed after both 5 and 10 mg/kg of DMCM (34 and 33%, respectively) compared with animals receiving pentobarbital alone (6%). Two doses of DMCM (5 and 2.5 mg/kg, respectively) administered 55 min apart produced an even greater increase (58%) in 24-h survival rates. Doses of DMCM that increased 1- and 24-h survival were not lethal when administered alone, and were below the dose that produced convulsions in 50% (CD50) of the animals. The protective effects of DMCM were blocked by pretreatment with the benzodiazepine receptor agonist ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo- 4H-imidazo[1,5a][1,4]benzodiazodiazepine-3-carboxylate (Ro 15-1788), which suggests the effects of DMCM are mediated through the benzodiazepine receptor. These findings suggest that DMCM or another benzodiazepine receptor ligand with full inverse agonist qualities could prove effective as an antidote for barbiturate intoxication in man.

Effect of regulatory withdrawal of drugs and prescription recommendations on the pattern of self-poisonings in Oslo.

A two-year prospective study of 1350 admissions for self-poisoning, covering the Oslo area was undertaken to identify the sources of the toxic agents. After the first year of the study, four barbiturates were withdrawn from the Norwegian market and recommendations were made by the Health Authorities to promote more restrictive attitudes when prescribing psychoactive drugs. The patterns of self-poisonings in the two periods were compared. The withdrawal of four barbiturates resulted in a 55% decrease in the rate of barbiturate poisonings in general (p less than 0.001). No increase could be detected in the rate of self-poisoning with benzodiazepines and other hypnotics, but the incidence of self-poisonings with antidepressants (p less than 0.01) and neuroleptics (p less than 0.01) was found to have increased significantly. The regulations and recommendations resulted in a significant decrease in drugs obtained from doctors randomly consulted (p less than 0.01), and a significant increase in drugs prescribed by psychiatrists (p less than 0.01). Drugs obtained from non-medical sources increased from 28% in the first period to 33.2% in the second. The total number of admissions and toxic agents taken remained unaltered. Thus, regulatory measures can influence the pattern of self-poisoning but do not seem to influence the tendency to abuse drugs or to take an overdose.

Serum thyroid hormones and tissue 5'-monodeiodinase activity in acutely thyroidectomized newborn lambs.

After either total thyroidectomy or sham operation in full-term fetal sheep, fetuses were delivered and serial blood samples were obtained for measurements of thyroxine (T4), triiodothyronine (T3), and catecholamines. Despite comparable serum T4 values (T4 means +/- SE, sham 7.1 +/- 0.6 micrograms/dl, thyroidectomized 6.8 +/- 0.7 micrograms/dl at 60 min after birth), serum T3 values were lower in the thyroidectomized animals (T3 means +/- SE, thyroidectomized 39 +/- 4.8 ng/dl, sham 153 +/- 20.1 ng/dl at 60 min after birth). Four hours after birth, the animals were killed with an intravenous overdose of barbiturate. Brain, thyroid, liver, kidney, and brown adipose tissues were dissected and analyzed for thyroxine 5'-monodeiodinase (5'-MDI) activity in vitro. 5'-MDI activity was comparable in all tissues from sham-operated and thyroidectomized lambs. Plasma epinephrine and norepinephrine concentrations, mean arterial pressure, mean pulse, rectal temperature, and arterial blood gas values were similar in the two groups of animals. These data support the hypothesis that the thyroid gland is the major source of T3 for the T3 surge in the immediate newborn period. They also indicate that the neonatal T3 surge has limited immediate metabolic significance in euthyroid newborns.

Barbiturate and Nonbarbiturate Sedative Hypnotic Intoxication in Children

This article reviews the pharmacology, toxicology, and treatment of both barbiturate and nonbarbiturate sedative hypnotic overdose. Although poisoning with these agents has declined over recent years, intoxication with them can still result in a life-threatening situation requiring immediate assessment and treatment.

Serum strontium estimation as a diagnostic criterion of the type of drowning water

The estimation of serum strontium in rabbits before and after death by drowning, in soft or hard water, or by barbiturate intoxication is highly promising as a method in medicolegal practice. It not only diagnoses drowning but also indicates the type of drowning water. Atomic absorption spectrophotometry is a good method for the estimation.

Postmortem evaluation of barbiturate poisonings

The evaluation of barbiturate intoxication as the cause of death is often difficult when the concentration in body fluids and organs is not extremely high. The problem arises because of the great capacity of barbiturates to produce tolerance after chronic use, a property that is often unknown. Therefore, the most abused barbiturates were studied to assess whether chronic intake causes morphological liver changes or not. It was found that the chronic abuse of drugs containing seco-, cyclo-, brallo-, and/or pentobarbital produces hypertrophy of the smooth endoplasmic reticulum of hepatocytes corresponding to that of phenobarbital. Neither acute barbiturate overdose (without a history of abuse) nor chronic abuse of opiates causes similar liver changes. In conclusion, barbiturate tolerance can be evaluated postmortem by light microscopic examination of the liver.

Poisoning-associated deaths for England and Wales between 1973 and 1980.

The annual number of deaths in England and Wales associated with poisoning by solids and liquids over the 8-year period between 1973 and 1980 has remained fairly constant with an average of 2897. Marked trends in the number of deaths associated with specific drugs are evident and apparently reflect prescription trends and drug availability. Barbiturate poisonings dropped steadily following the downward trend in barbiturate prescriptions. Deaths associated with dextropropoxyphene, paracetamol and certain benzodiazepines increased dramatically.

Acute chlormethiazole poisoning in patients notified to the Poisons Unit, Guy's Hospital, 1978--1981.

1 Out of 493 patients with suspected acute chlormethiazole poisoning notified to the Poisons Unit, Guy's Hospital during 1978--1981, the diagnosis was confirmed either analytically or by detailed clinical information in 108 patients, 40 of whom had ingested chlormethiazole alone. 2 The principal signs reported indicate that the clinical features of acute chlormethiazole poisoning resemble those of barbiturate poisoning, with deep coma (n = 66), respiratory depression (n = 26) and hypotension (n = 17) in the severe cases. Five patients died as a result of early, profound respiratory depression. 3 In 53 survivors in whom toxicological analyses were performed, poisoning with chlormethiazole alone had a better prognosis than when ethanol or other drugs were also present, except in patients with hepatic or pulmonary disease or in the elderly. 4 These results emphasise that although patients poisoned with chlormethiazole who survive to reach hospital generally have a good prognosis, fatal respiratory complications often occur before the patient can be treated.

Periodic EEG discharges in psychiatry.

Periodic EEG discharges are signs of severe CNS dysfunction. In psychiatry they usually indicate presenile dementia of the Jacob-Creutzfeldt type. Psychiatric patients are presented in whom the occurrence and EEG features of diffuse and lateralized periodic discharges are discussed. It appears that toxic conditions other than acute barbiturate intoxication, such as drug withdrawal states and psychotropic drug overdosage, represent important etiological factors for inducing periodic EEG discharges. Their relation to clinical signs such as epileptic symptoms, metabolic dysfunction, and disturbance of consciousness is particularly stressed and related to current literature data.

L'EEG dans le pronostic des comas toxiques: reflexions a propos de quelques donnees inhabituelles

During acute intoxications, the first EEG may show persistence or abolition of cerebral activity, but the possibility of recovery after isoelectric tracing in toxic comas must be emphasized. EEG patterns frequently suggest the probability of hypnotic tranquilizer poisoning; 4 types of EEG are encountered corresponding to different grades of toxic coma. Recurrent periods of electrical silence alternating with bursts of activity are habitually recorded in carus comas with hypothermia due to acute barbiturate intoxication, with good prognosis. The possibility of a neurological disturbance associated with drug overdose must be raised whenever an asymmetric tracing is encountered. Serial recordings may detect complications such as: a localized lesion, anoxia or, very rarely, typical paroxysmal abnormalities reappearing in comitial patients before emergence from a toxic coma. Paradoxical monomorphic delta activity corresponding to improvement must not be considered as an aggravation. Peculiar EEG findings occur after oral trichlorethylene poisoning, with temporary clinical deterioration and intermittent periods of electrical silence; recovery is possible. An alpha-like pattern after cardiac arrest of toxic origin has a poor prognosis. The appearance of alternating patterns suggests the development of irreversible brain damage.

Oxygen transport, consumption and utilization during barbiturate intoxication.

Factors related to oxygen availability and requirements were measured on 51 occasions in 14 patients intoxicated with short-acting barbiturates. Patients had no clinical signs of circulatory shock. The cardiac index was normal (3.4 +/- 1.1 1/min/m2) but there was a slight decrease of the mean arterial oxygen content (17.2 +/- 3.0 ml/100 ml). Oxygen transport was normal (571 +/- 199 ml/min/m2). However, the arteriovenous oxygen differences were decreased (3.4 +/- 1.0 ml/100 ml). Oxygen consumption was reduced (110 +/- 42 ml/min/m2) and the oxygen extraction ratio (oxygen consumption/oxygen transport) was decreased (0.20 +/- 0.05), thus confirming a decreased oxygen utilization. Arterial concentration of lactate was normal. Accordingly the observed decrease in oxygen consumption was related to a reduction in oxygen requirements during barbiturate intoxication rather than due to an imbalance between availability and metabolic requirements for oxygen.

Pulmonary toxicity following gastrointestinal ingestion of kerosene

The continuous controversy concerning the treatment for acute hydrocarbon ingestions led to a study of the pulmonary effects of kerosene absorption from the gastrointestinal tract in dogs. Gastrostomies and cervical esophageal transections with a proximal esophageal fistula were performed on 11 dogs under general anesthesia. Following a return of normal bowel function each animal was given 20 cc/kg of a commercial-grade kerosene by gastrostomy tube. The dogs were randomly divided into two groups for necropsy at 24 and at 72 hours, and each dog had chest radiographs prior to instillation of the kerosene and at 6, 24, 48, and 72 hours, depending on their group. The dogs were given an overdose of barbiturate for euthanasia. Tissue was randomly selected from the lungs and examined using standard microscopic and histologic techniques. No clinical complications were observed in any of the animals following the kerosene instillation. No radiologic or histologic evidence of pulmonary changes due to kerosene was found. The lack of pulmonary pathologic changes following kerosene ingestion in dogs protected from aspiration suggests that the treatment for kerosene poisoning should be confined to supportive measures. Induction of emesis is contraindicated in the management of hydrocarbon ingestion.