Barbiturates, smoking, and bladder cancer risk.

Habel LA, Bull SA, Friedman GD.

Division of Research, Kaiser Permanente Medical Care Program, Oakland, California 94611, USA. lah dor.kaiser.org

Phenobarbital treatment has been observed to be negatively associated with bladder cancer risk in a few studies. It has been suggested that phenobarbital may induce drug-metabolizing enzymes that detoxify the bladder carcinogens found in cigarette smoke. We examined the relationship of barbiturate use to bladder cancer risk and the potential modifying effect of cigarette smoking in a large cohort of Kaiser Permanente Medical Care Program members with computerized pharmacy prescriptions and smoking information. Newly diagnosed bladder cancers were identified among individuals in the study cohort by linkage with data from cancer registries. The overall standardized incidence ratio associated with barbiturate use was 0.71 [95% confidence interval (CI), 0.51-0.99]. Among current smokers, former smokers, and never smokers, the standardized incidence ratios were 0.56 (95% CI, 0.23-1.16), 0.68 (95% CI, 0.27-1.40), and 1.04 (95% CI, 0.48-1.98), respectively. Although our estimates were imprecise, the finding of an inverse association between barbiturate treatment and bladder cancer risk only among current and former cigarette smokers is consistent with the hypothesis that treatment with these medications induces drug-metabolizing enzymes that deactivate bladder carcinogens found in cigarette smoke.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9829715&dopt=Abstract barbiturate Butalbital Fioricet





Barbiturate coma may promote reversible bone marrow suppression in patients with severe isolated traumatic brain injury.

Stover JF, Stocker R.

Division of Trauma Surgery, Zurich University Hospital, Switzerland.

OBJECTIVES: Barbiturate coma is employed in brain-injured patients whenever increases in intracranial pressure remain unresponsive to less aggressive therapeutic regimens. Barbiturate-mediated neuroprotection, however, is weakened by an increased infection rate related to barbiturate-induced immunosuppression. Co-administration of barbiturates with antibiotics known to induce bone marrow suppression could, in turn, potentiate barbiturate-mediated immunosuppression. Adverse drug reactions and interactions of thiopental with antibiotics in terms of leukopenia, infection rate, and bone marrow suppression were investigated. METHODS: White blood cells were measured daily, tracheobronchial secretion and urine were examined for bacterial growth twice a week or if an infection was suspected. RESULTS: A total of 52 patients with severe isolated head injury were consecutively investigated. Due to increased intracranial pressure (ICP), which did not respond to analgosedation, barbiturate coma was performed in 23 cases. The other 29 patients remained analgosedated. Leukocytes and neutrophils were reversibly and significantly decreased in all patients, mostly sustained under thiopental. The pulmonary infection rate due to gram-negative organisms was nearly doubled during barbiturate coma. Reversible agranulocytosis and bone marrow suppression attributed to antibiotics developed in six patients after thiopental administration. Mortality rate, however, was not increased by these adverse effects. CONCLUSIONS: Barbiturate coma may cause reversible leukopenia and an increased infection rate. Long-term administration of thiopental may also promote reversible antibiotic-induced bone marrow suppression. The mechanisms and site of interaction between thiopental and antibiotics cannot be assessed by the present study and remain to be clarified. However, during and after barbiturate coma, close monitoring of leukocytes and infections and careful selection of antibiotics is required.

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Benzodiazepine and barbiturate ligands modulate responses of cultured hippocampal neurones to the GABAA receptor partial agonist, 4-PIOL.

Kristiansen U, Lambert JD.

Department of Biology, Royal Danish School of Pharmacy, Copenhagen, Denmark.

We have previously characterized 5-(4-piperidyl)isoxazol-3-ol (4-PIOL) as a non-desensitizing partial agonist at GABAA receptors and shown that the responses are mediated by short-duration channel openings consonant with single-ligand gated openings of the Cl- channels. We presently investigate whether responses of cultured rat hippocampal neurones to 4-PIOL are modulated by benzodiazepine (BDZ) and barbiturate receptor ligands. Whole-cell patch-clamp recordings of maximal responses to 1 mM 4-PIOL were comparable in size to responses evoked by 10 microM of the full GABAA agonist, isoguvacine. The BDZ receptor inverse agonist, DMCM (1 microM) reduced responses to isoguvacine (to 65.7 +/- 11.0%) and 4-PIOL (to 69.3 +/- 3.5%) to a similar extent. The BDZ agonist, midazolam (0.1 microM) potentiated responses to both agonists, and resulted in responses with an early peak with later fading. Potentiation of the peak response to 4-PIOL (to 163 +/- 14%) was significantly less than for isoguvacine (215 +/- 11%). Pentobarbital (50 microM) caused a very marked, but variable, potentiation of the peak response to 4-PIOL (to 484 +/- 93%), which was significantly greater than the potentiation of the peak response to isoguvacine (to 304 +/- 46%), and induced fading. This suggests that a relatively larger number of the 4-PIOL-induced channel openings can be transformed to longer duration openings by pentobarbital. In conclusion, responses to 4-PIOL and isoguvacine are modulated by BDZ and barbiturate ligands in a qualitatively similar manner, but with a number of quantitative differences which cannot be readily explained by the kinetic model of Macdonald and Twyman (1992). Investigation of these responses at the single-channel level could provide further insight into the operation of the GABAA receptor-ionophore complex.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9014133&dopt=Abstract barbiturate Butalbital Fioricet





[The inhibition of lidocaine metabolism by various barbiturates in rat hepatic microsome]

[Article in Japanese]

Kakinohana M, Taira Y, Kakinohana O, Okuda Y.

Department of Anesthesiology, Faculty of Medicine, University of the Ryukyus, Okinawa.

To evaluate the effects of various barbiturates on lidocaine metabolism by cytochrome P-450 (P-450), enzyme kinetics were analyzed in an in vitro study using rat hepatic microsomes. Phenobarbital, amobarbital, hexobarbital, pentobarbital, and thiamylal showed the mixed type inhibition of lidocaine metabolism with inhibition constants being 4.89, 1.08, 2.76, 0.77 and 0.65 mM, respectively. Same as lidocaine, all barbiturates used in the present study, corresponding to binding with P-450, induced the I type of spectral change of P-450. Since these did not affect cytochrome C reductase activity, it was suggested that this inhibition of lidocaine metabolism in hepatic microsomes may have been caused by the reduction of activity on P-450 by the barbiturates.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9852692&dopt=Abstract barbiturate Butalbital Fioricet