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Biomedical subjects

J M Baden

Publications and source records attributed to J M Baden.

At least 55 records · Page 3Linked to original sources

Inhaled anaesthetics have no effect on fertility in Drosophila melanogaster.

The potential effects of enflurane, isoflurane, halothane, fluroxene and nitrous oxide on mortality and fertility in Drosophila melanogaster were examined. The LD50 value 1 day after exposure for 1 h was the same for males and females and was about 8% for enflurane, isoflurane and halothane, about 20% for fluroxene, and greater than 100% for nitrous oxide. Male and female fertility, however, were not affected by any of the anaesthetics, even at concentrations well above those used clinically.

Anesthesia, Inhalation↗

Halothane anesthesia does not exacerbate hepatic dysfunction in cirrhotic rats.

The authors have refined a model of cirrhosis in the rat and used it to determine whether the administration of halothane anesthesia adversely affects preexisting liver disease. Male Wistar rats were placed on phenobarbital water and were assigned randomly to two groups. Group 1 rats were exposed by inhalation to carbon tetrachloride (CC14) at weekly intervals for 12 exposures while Group 2 rats received only air. All treatment including phenobarbital then was withdrawn for 4 weeks. Rats then were bled for SGOT and SGPT determinations and 24 h later were exposed to 1.8% halothane in oxygen for 3 h (HAL); the remaining rats from each group were exposed to 100% oxygen for 3 h (O2). Twenty-four hours later, rats were killed and blood was obtained for SGOT and SGPT by cardiac puncture. Light microscopic histologic examination was performed blind on liver sections for cirrhosis and scored for superimposed acute focal necrosis. The weekly sublethal CCl4 exposure resulted in histologically demonstrable cirrhosis in all surviving Group 1 animals. The mean (+/- SD) SGOT (128 +/- 32 IU/1) and SGPT (86 +/- 24 IU/1) values for the Group 1 rats were significantly greater (P less than 0.01) than those for Group 2 rats (98 +/- 18 IU/1 and 57 +/- 12 IU/1, respectively). Cirrhotic animals showed neither deterioration in liver function nor acute liver cell necrosis after Hal compared with O2. However, Group 2 rats showed a modest but significant increase in SGOT (P less than 0.05) after HAL, while this change was not noted after O2. Thus, 1.8% halothane anesthesia in oxygen did not result in superimposition of acute liver cell injury in already cirrhotic rats.

Alanine Transaminase↗

Mutagenicity of inhaled anesthetics in Drosophila melanogaster.

The mutagenic effects of several inhaled anesthetic agents were investigated using the sex-linked recessive lethal assay in the fruit fly, Drosophila melanogaster. Male wild-type flies were exposed for 1 hr to either halothane, enflurane, isoflurane, or fluroxene at vapor concentrations of 1 or 2% or to nitrous oxide at concentrations of 40 or 80%. Control flies were exposed to air alone. Following treatment, male flies were mated with untreated virgin females of the Basc strain and the rate of sex-linked recessive lethals was determined in the F2 generation. Halothane and fluroxene produced a dose-dependent and statistically significant increase in the rate of sex-linked recessive lethals, whereas enflurane, isoflurane, and nitrous oxide were not mutagenic at the concentrations tested.

Anesthesia, Inhalation↗

Halothane, isoflurane, and enflurane MAC in pregnant and nonpregnant female and male mice and rats.

The MAC of halothane, isoflurane, and enflurane was determined using the tail-clamp technique in pregnant female, nonpregnant female, and male Swiss Webster mice (n = 216) and Sprague-Dawley rats (n = 112). Mean MAC values (+/-SD) for halothane, isoflurane, and enflurane in mice were 0.95 +/- 0.07%, 1.34 +/- 0.10%, and 1.95 +/- 0.16%, respectively; values in rats were 1.03 +/- 0.04%, 1.46 +/- 0.06%, and 2.21 +/- 0.08%, respectively, all significantly higher than in mice. Neither the sex of the animals nor whether female animals were pregnant influenced the results.

Anesthesia, Inhalation↗

Effects of volatile anesthetics or fentanyl on hepatic function in cirrhotic rats.

Halothane, enflurane, isoflurane, and fentanyl were examined for their potential to exacerbate liver dysfunction in rats with preexisting cirrhosis. Male Wistar rats given sodium phenobarbital for 2 weeks are assigned randomly to two groups. One group (cirrhotic) was exposed by inhalation to carbon tetrachloride (CCl4) in air at weekly intervals for 12 weeks to induce cirrhosis. The other group (noncirrhotic) was handled similarly but received air only. Five weeks after the last exposure to CCl4, cirrhotic and noncirrhotic rats were given three hours of 1 MAC halothane, enflurane, or isoflurane in 50% oxygen, or 350 micrograms fentanyl per kg of body weight and 50% oxygen, or 50% oxygen only. Blood gas tensions and blood glucose levels were measured before, during, and at the end of exposure. Forty-eight hours after exposure, serum chemistries were measured in each rat for comparison with preexposure values. Rats were then killed by CO2 overdose, and liver, kidney, and testis were prepared for microscopic examination. Enflurane, isoflurane, and halothane, but not fentanyl, produced mild respiratory acidosis and no change in serum glucose levels. All anesthetics resulted in a mild but similar degree of acute liver dysfunction as indicated by small increases in SGOT or SGPT in both cirrhotic and noncirrhotic rats. Liver histology revealed mild to moderate portal cirrhosis with fibrosis and well-developed micronodules in rats exposed to CCl4, but no superimposed acute hepatocellular damage was noted. It is concluded that all the anesthetics used in this study were associated with the same minimal degree of postanesthetic hepatic dysfunction and that the dysfunction was similar in both cirrhotic and noncirrhotic rats.

Alanine Transaminase↗

Reproduction and fetal development in rats exposed to nitrous oxide.

The effects of 24 hours of nitrous oxide exposure on reproductive indices and fetal development were examined in Sprague-Dawley rats. Four different experiments employing four concentrations of nitrous oxide--0.75%, 7.5%, 25% and 75%--established that the threshold of toxicity was greater than 25%. At 75% nitrous oxide there was a significant increase in early and late resorptions, and a consistent teratogenic effect (e.g., runts, ocular malformations, limb deformities). Neither the stress of shipping dams while pregnant nor the withholding of food during nitrous oxide exposure resulted in additional adverse effects. Exposure to 25% nitrous oxide was associated with increased deoxyuridine suppression values; however, adverse reproductive effects were not seen at this nitrous oxide concentration. The results of this and other studies which have examined the reproductive and teratogenic effects of nitrous oxide do not contraindicate its use in operating rooms nor, when necessary, as an anesthetic for pregnant surgical patients.

Abnormalities, Drug-Induced↗

Inhibition of fetal methionine synthase by nitrous oxide.

The activity of the enzyme methionine synthase in fetal and maternal liver was investigated before and after exposure to nitrous oxide. Timed-pregnant rats on day 19 of gestation were exposed to either 10% or 50% nitrous oxide for various times up to 240 min. After exposure, fetal and maternal livers were removed and methionine synthase activity assayed. Normal methionine synthase activity in the fetus was about 50% of that in the mother. Both fetal and maternal methionine synthase activity decreased progressively with increasing time of exposure to nitrous oxide and recovered only slowly after the agent was discontinued.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

Nitrous oxide inactivates methionine synthetase activity in rat testis.

Methionine synthetase (MS) activity in the brain and liver is decreased following nitrous oxide (N2O) exposure. Since MS is important for DNA synthesis, this interaction would be expected to have the most serious consequences on actively replicating tissue. The authors therefore measured MS activity in rat testes following 1 h exposure to either 10% or 50% N2O. Animals exposed to 10% N2O had a 29% reduction in MS activity, and exposure to 50% N2O caused a 63% reduction in enzyme activity. Testicular MS activity returned to normal by 24-48 h in the 10% exposure group and by 72 h in the 50% exposure group. This biochemical effect on testicular enzyme activity could be the basis for the reported deleterious effects of N2O on spermatogenesis.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

Germ cell studies in mice after prolonged exposure to nitrous oxide.

Male and female Swiss Webster (SW) mice, age 13 to 14 weeks, were exposed by inhalation for 4 hr per day, 5 days per week, for 14 weeks, to either room air, 0.5% nitrous oxide, 5.0% nitrous oxide, or 50% nitrous oxide. Murine germ cells were examined for evidence of injury after this exposure. A group of male mice were treated with methyl methanesulfonate (MMS) as a positive control for sperm abnormalities while a group of female mice were treated with 3-methylcholanthrene (3-MC) as a positive control for oocyte destruction. There were no significant differences among the four inhalation exposure groups in testes weight, percentage of abnormally shaped sperm, sperm count, or histologic appearance of the testes; the mean percentage (+/- SE) of abnormal sperm ranged from 8.9 +/- 2.4 (5.0% nitrous oxide) to 13.5 +/- 0.5 (50% nitrous oxide) with a concurrent control value of 10.4 +/- 2.3%. In the positive control experiment, 25.2 +/- 4.1% of sperm from mice treated with MMS were abnormal compared with 2.5 +/- 0.3% of sperm from mice treated with saline (p less than 0.001), indicating that sperm of SW mice are sensitive to chemical damage. There was no significant difference between the mean number of oocytes in mice treated with 50% nitrous oxide (33.3 +/- 14.4) and in control mice (29.8 +/- 8.0). In the positive control experiment, mice treated with 3-MC had significantly fewer (p less than 0.001) primordial oocytes, 67.2 +/- 19.5 compared with control mice, 222.4 +/- 21.9, indicating that this strain is sensitive to chemical damage of the ovary. Thus, murine germ cells showed no evidence of toxic effects due to prolonged exposure to nitrous oxide.

Anesthesiology↗

Thymidine and methionine syntheses in pregnant rats exposed to nitrous oxide.

The dose-dependent effects of nitrous oxide on thymidine and methionine syntheses were investigated in pregnant rats. Female Sprague-Dawley rats were exposed on day 9 of gestation to 0.75%, 7.5%, or 75% nitrous oxide for 24 h. Immediately and 72 h after exposure, a deoxyuridine-suppression test was performed on maternal bone marrow and a methionine synthetase assay was performed on maternal liver to assess thymidine and methionine syntheses, respectively. Inhibition of thymidine synthesis was seen after exposure to 7.5% and 75%, but not after 0.75%, nitrous oxide. Recovery was complete 72 h after exposure. Methionine synthetase activity was abolished at all concentrations of nitrous oxide tested and did not return to control values 72 h after exposure. Fetal weight and gross appearance were not affected by exposure to nitrous oxide; however, the observed decrease in thymidine and methionine syntheses after nitrous oxide exposure may account for its teratogenic effects.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

Reproduction and fetal development in mice chronically exposed to nitrous oxide.

The effects of exposure to nitrous oxide on reproductive indices, fetal development, and male fertility were examined in Swiss/ICR mice. In experiment I, female mice were exposed for 4 hours per day on days 6-15 of pregnancy, to 0.5% (5,000 ppm), 5.0% (50,000 ppm), or 50% (500,000 ppm) nitrous oxide. Control mice were untreated, exposed to compressed air, or treated with retinoic acid on day 8 of gestation. In experiment II, male mice were treated, as above, for 9 weeks and then mated nightly for 7 nights to untreated, virgin females. In experiment I, 1,761 fetuses from 154 dams were examined and found to be without evidence of adverse nitrous oxide treatment effects. In experiment II there were no differences among the groups in the ability of males to impregnate females or in litter size, fetal wastage, or fetal size. When we compare nitrous oxide with other inhalation anesthetics we have studied employing a similar protocol, we find the order of reproductive toxicity to be: halothane greater than enflurane greater than methoxyflurane greater than nitrous oxide. None of the agents were toxic, however, at the trace concentrations usually found in operating rooms.

Abnormalities, Drug-Induced↗

Carcinogen bioassay of enflurane in mice.

A carcinogen bioassay of enflurane was performed in Swiss/ICR mice. Two groups of weanling mice, each of 125 males and 125 females, were exposed to eigher a maximum tolerated dose of enflurane, 3000 ppm (0.3 per cent v/v) or compressed air for 4 hs per day, 5 days per week. After 52 weeks exposure, 25 males and 25 females from each group were killed. After 78 weeks exposure, a 4-week period without treatment was allowed before the remaining mice were killed. Mice killed at the scheduled periods and those killed or dying at other times throughout the study, underwent extensive gross and histologic, examinations unless autolysis or cannibalism precluded examination. After 78 weeks exposure, male mice in the enflurane-treated group had a 36 per cent incidence of liver tumors compared with 24 per cent in the control group; however, the difference was no statistically significant. The incidence of lung tumors was about 20 per cent in all groups. Other neoplastic lesions occurred in small numbers and were unrelated to treatment. It was concluded that under the conditions of the present experiment, chronic administration of enflurane at its maximum tolerated dose did not lead to an increased incidence of neoplasia in Swiss/ICR mice.

Adenoma↗

Deuterated methoxyflurane anesthesia and renal function in Fischer 344 rats.

Inorganic fluoride (F-) production and renal function were assessed in six groups of Fischer 344 rats administered either methoxyflurane (MOF) or deuterated methoxyflurane (d4-MOF). One untreated and one phenobarbital (PB)-treated group were exposed for two hours to either air, 0.5 per cent (V/v) MOF, or 0.5 per cent (v/v) d4-MOF. Serum and urinary F- and serum urea nitrogen and creatinine were measured. Urine volume and urinary F- excretion were only slightly greater among MOF than among d4-MOF exposed animals. Pretreatment with PB, however, greatly enhanced F- production in MOF-exposed animals leading to marked renal impairment but only slightly enhanced F- production in d4-MOF animals leading to mild renal impairment. Thus, only in PB-pretreated animals could a biologically significant difference in nephrotoxicity be demonstrated for MOF and d4-MOF.

Anesthesia↗

Mutagenicity of experimental inhalational anesthetic agents: sevoflurane, synthane, dioxychlorane, and dioxyflurane.

A modification of the Ames bacterial assay system employing two histidine-dependent strains of Salmonella typhimurium, TA1535 and TA100, was used to test the mutagenicity of four experimental, inhalational anesthetic agents: sevoflurane, synthane, dioxychlorane, and dioxyflurane. None of the anesthetics was mutagenic. Increased activity was seen only with vinylidene chloride, the positive control.

Anesthetics↗

Reduction in fertility of male mice after exposure to high environmental pressure.

Male mice were exposed to 50 ATA heliox pressure to study whether their functional fertility was affected. In series I, control mice were exposed to 1 ATA air; in series II controls were exposed to 5 ATA heliox, which enabled the PO2 and environmental temperature to be maintained at equivalent levels to the pressure group. After exposure during one spermatogenic cycle, the mice were mated with untreated females. There was a dramatic reduction in fertility in the pressure groups, with males in both series I and II showing a 65% reduction in fertility. Overall results were as follows: 19.5% pregnant females mated with the pressure groups compared with 55% pregnant in the control groups. Litter sizes in the pressure groups were reduced by 44%, but there was no evidence of any pressure-related teratological effect. This reduction in fertility appears to be due to high pressure per se and not to the high environmental temperature and PO2 associated with heliox atmospheres.

Animals↗

Lack of toxicity of enflurane on male reproductive organs in mice.

Enflurane has been shown to increase slightly the percentage of abnormal spermatozoa in mice. To examine in more detail possible adverse effects of enflurane on male reproductive organs, 125 Swiss/ICR mice were exposed to 0.3% enflurane for up to 18 months; a control group of 125 mice was exposed concurrently to air. Exposures were for 4 hours/day, 5 days/week. After 12 months of exposure, groups of 25 enflurane-treated and control mice were killed, and chromosomal analysis of spermatogonial cells was performed. After 18 months exposure, remaining mice were killed and epididymal sperm were collected for morphologic examination. In addition, the reproductive organs of all mice dying or killed throughout the study were examined histologically. Approximately 1% of spermatogonial cells from both enflurane-treated and control mice had aberrant chromosomes. The average percentage of morphologically abnormal sperm was 9.4 +/- 1.7 for enflurane-treated mice and 6.5 +/- 1.3 for control mice; the difference was not statistically significant (p = 0.18). Finally, there was no difference between the treated and control mice in histologic appearance of reproductive organs. It was concluded that long-term exposure to enflurane has no adverse effects on male reproductive organs in mice.

Animals↗

Mutagenicity and toxicity studies with high pressure nitrous oxide.

The mutagenic and toxic potential of nitrous oxide were assessed in vitro by microbial assay using two histidine dependent strains of Salmonella typhimurium, TA98 and TA100. Bacteria on plates and in liquid suspension in the presence or absence of enzymes prepared from rat liver, were exposed in a pressure chamber to partial pressures of nitrous oxide ranging from 0.5 to 6 atmospheres. Nitrous oxide decreased viability of both strains of bacteria at 4 and 6 atmospheres but was not mutagenic at any pressure tested.

Animals↗

Effect of high helium and hydrostatic pressure on bacterial mutation and growth.

The mutagenic and toxic effect of high helium and hydrostatic pressure were assessed in an in vitro microbial assay using two histidine-dependent strains of Salmonella typhimurium. TA98 and TA100. Bacteria in the presence or absence of mammalian enzyme system were subjected to either 50 or 100 atmospheres absolute (ATA) helium or 300 ATA hydrostatic pressure. The number of revertant colonies, colony forming units and cell growth rates were measured. There was no mutagenic effect of decrease in number of colony forming units at any of the pressures tested. However, a statistically significant decrease in growth rate of exponentially dividing cells was seen at 300 ATA hydrostatic pressure and 100 ATA helium, but not at 50 ATA helium.

Helium↗