Barbiturates and lung cancer: a re-evaluation.

Friedman GD, Habel LA.

Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA. gdf dor.kaiser.org

BACKGROUND: Barbiturates, particularly phenobarbital, have been shown to be a tumour promoter in animal experiments and were found to be associated with increased risk of lung cancer in our cohort follow-up study to screen pharmaceuticals for possible carcinogenic effects. Sixteen more years of follow-up have accumulated permitting a more detailed evaluation of this association. METHODS: In all, 10,213 subscribers of the Kaiser Permanente Medical Care Program who received barbiturates between 1969 and 1973 from its San Francisco pharmacy were followed up through 1992 and their incidence of lung cancer at biennial intervals was compared with what was expected based on the experience of the entire pharmacy cohort (143,594). Smoking-habit data were available on about half of the barbiturate users and were used to adjust for cigarette smoking in both the observed/expected analysis and in Cox proportional hazards analysis. RESULTS: The initially elevated standard morbidity ratio of 1.55 (95% CI: 1.25-1.91) with 3-7 years of follow-up gradually decreased and stabilized at about 1.3 after 11-15 years of follow-up. This trend for diminishing relative risk over time was more pronounced among the never smokers but their initial excess risk was not statistically significant due to small numbers. A dose-response trend was observed, based on the number of prescriptions dispensed. Analytical control for cigarette smoking reduced but did not eliminate either the association or the dose-response trend. Most of the barbiturate-associated cases in never smokers were women and the predominant histological type was adenocarcinoma. CONCLUSIONS: These findings from up to 23 years of follow-up are not conclusive because of the continuing small number of never smokers who developed lung cancer. However, they strengthen and refine previous observations of a barbiturate-lung cancer association, which is probably not fully explained by confounding by cigarette smoking. The diminution of excess risk over time is consistent with a tumour promoter effect. Findings among the never smokers suggest that this possible effect may be greatest on adenocarcinomas in women.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10405836&dopt=Abstract barbiturate Butalbital Fioricet





Acute cellular alterations in the hippocampus after status epilepticus.

Macdonald RL, Kapur J.

Department of Neurology, University of Michigan Medical Center, Ann Arbor 48104-1687, USA.

The critical, fundamental mechanisms that determine the emergence of status epilepticus from a single seizure and the prolonged duration of status epilepticus are uncertain. However, several general concepts of the pathophysiology of status epilepticus have emerged: (a) the hippocampus is consistently activated during status epilepticus; (b) loss of GABA-mediated inhibitory synaptic transmission in the hippocampus is critical for emergence of status epilepticus; and, finally (c) glutamatergic excitatory synaptic transmission is important in sustaining status epilepticus. This review focuses on the alteration of GABAergic inhibition in the hippocampus that occurs during the prolonged seizures of status epilepticus. If reduction in GABAergic inhibition leads to development of status epilepticus, enhancement of GABAergic inhibition would be expected to interrupt status epilepticus. Benzodiazepines and barbiturates are both used in the treatment of status epilepticus and both drugs enhance GABA(A) receptor-mediated inhibition. However, patients often become refractory to benzodiazepines when seizures are prolonged, and barbiturates are often then used for these refractory cases of status epilepticus. Recent evidence suggests the presence of multiple GABA(A) receptor isoforms in the hippocampus with different sensitivity to benzodiazepines but similar sensitivity to barbiturates, thus explaining why the two drug classes might have different clinical effects. In addition, rapid functional plasticity of GABA(A) receptors has been demonstrated to occur during status epilepticus in rats. During status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. The loss of sensitivity of the animals to diazepam during status epilepticus was accompanied by an alteration in the functional properties of hippocampal dentate granule cell GABA(A) receptors. Dentate granule cell GABA(A) receptor currents from rats undergoing status epilepticus had reduced sensitivity to diazepam and zinc but normal sensitivity to GABA and pentobarbital. Therefore, the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABA(A) receptors, possibly explaining why benzodiazepines and barbiturates may not be equally effective during treatment of the prolonged seizures of status epilepticus. A comprehensive understanding of the cellular and molecular events leading to the development, maintenance, and cytotoxicity of status epilepticus should permit development of more effective treatment strategies and reduction in the mortality and morbidity of status epilepticus.

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gamma-aminobutyric acidA receptor regulation: heterologous uncoupling of modulatory site interactions induced by chronic steroid, barbiturate, benzodiazepine, or GABA treatment in culture.

Friedman LK, Gibbs TT, Farb DH.

Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, MA 02118-2394, USA.

Prolonged administration of anxiolytic, sedative, and anticonvulsant drugs that act through the GABAA receptor (GABAAR) can evoke tolerance and dependence, suggesting the existence of an endogenous mechanism(s) for altering the ability of such agents to interact with the GABAAR. Uncoupling appears to be one such mechanism. This is a decrease in the allosteric interactions between the benzodiazepine (BZD) recognition site and other agonist or modulator sites on the GABAAR, as measured by potentiation of [3H]flunitrazepam ([3H]FNZ) binding. To investigate the mechanism(s) of uncoupling, neuronal cultures were treated chronically with 3 alpha-hydroxy-5 beta-pregnan-20-one (pregnanolone), pentobarbital, flurazepam, or GABA, then tested for enhancement of [3H]FNZ binding by these substances. The results indicate that BZDs, barbiturates, and steroids, as well as GABA itself, are capable of inducing both heterologous and homologous uncoupling. Surprisingly, different chronic drug treatments produce different patterns of homologous and heterologous uncoupling. Chronic exposure to pregnanolone, GABA, flurazepam or pentobarbital induces complete uncoupling of barbiturate-BZD site interactions, partial uncoupling of GABA-BZD site interactions, but different amounts of uncoupling of steroid-BZD site interactions. In addition, the EC50 for pregnanolone-induced homologous uncoupling (1.7 microM) is over an order of magnitude greater than that for heterologous uncoupling of GABA and BZD sites (82 nM). Moreover, heterologous uncoupling by pregnanolone is inhibited by the GABA site antagonist SR-95531, whereas homologous uncoupling by pregnanolone is resistant to SR-95531. Therefore, there are at least two distinct ways in which GABAAR modulatory site interactions can be regulated by chronic drug treatment.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8866718&dopt=Abstract barbiturate Butalbital Fioricet





Thiopental attenuates energetic impairment but fails to normalize cerebrospinal fluid glutamate in brain-injured patients.

Stover JF, Pleines UE, Morganti-Kossmann MC, Stocker R, Kossmann T.

Department of Surgery, University Hospital Zurich, Switzerland.

OBJECTIVES: Brain-injured patients are susceptible to secondary brain damage related to decreased cerebral perfusion pressure associated with edema formation and increased intracranial pressure (ICP). Whenever conventional therapy fails to reduce elevated ICP, barbiturate coma represents an additional intervention that may control ICP. In patients suffering from severe traumatic brain injury, cerebrospinal fluid levels of glutamate, hypoxanthine, and lactate were measured during barbiturate coma and correlated to electroencephalographic recordings and ICP. DESIGN: Prospective, descriptive study. SETTING: Ten-bed surgical intensive care unit in a university hospital. PATIENTS: Twenty-one patients with severe traumatic brain injury (Glasgow Coma Scale score < or = 9); 11 required barbiturate coma because of refractory intracranial hypertension, and 10 were manageable with continuous administration of fentanyl and midazolam. INTERVENTIONS: Thiopental was administered continuously for increased ICP within the first 24 hrs after trauma and adjusted to the burst-suppression pattern (four to six bursts per minute) on continuous electroencephalographic monitoring. MEASUREMENTS AND MAIN RESULTS: Glutamate and hypoxanthine were analyzed using high-performance liquid chromatography, whereas lactate was measured enzymatically. Patients requiring thiopental presented with significantly higher ICP, glutamate, and hypoxanthine levels than patients receiving fentanyl and midazolam (p < .05). Within the first 24 hrs, thiopental significantly reduced cerebrospinal fluid glutamate and hypoxanthine levels in all patients, i.e., the burst-suppression pattern was successfully induced (p < .001). Interestingly, in five patients cerebrospinal fluid glutamate increased to initial values again despite unchanged neuronal activity. In these patients, ICP, hypoxanthine, and lactate remained significantly elevated compared with the six patients with steadily decreasing cerebrospinal fluid glutamate, hypoxanthine, lactate, and ICP values (p < .02). CONCLUSIONS: Barbiturate coma does not unequivocally preserve energetic stability despite successful suppression of neuronal activity. Despite the use of barbiturate coma in patients with refractory intracranial hypertension, persistent release or impaired uptake of glutamate may be associated with continuous anaerobic metabolism, as shown by increases in cerebrospinal fluid hypoxanthine and lactate levels.

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