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Biomedical subjects

R I Mazze

Publications and source records attributed to R I Mazze.

At least 19 recordsLinked to original sources
PubMed1992

Developmental toxicity of nondepolarizing muscle relaxants in cultured rat embryos.

Evidence of developmental toxicity of clinically used nondepolarizing muscle relaxants was sought in rat embryos grown in culture. Embryos were explanted at 8 AM on day 9 of gestation (presomite stage, plug day = day 0), and were cultured in rotating bottles with medium containing various concentrations of d-tubocurarine, pancuronium, atracurium, and vecuronium. At 10 AM on day 11 of gestation (forelimb bud stage), culture was terminated and embryos were examined for general morphology. Treatment with tested agents resulted in dose-dependent developmental toxicity; namely, growth retardation seen as decreased crown-rump length, decreased number of somite pairs, and morphologic abnormalities. However, the concentrations that caused toxicity were at least 30-fold greater than serum concentrations clinically achieved in the mother. We conclude that these muscle relaxants have a low potential for causing developmental toxicity during organogenesis.

Animals↗
PubMed1991

Preventive effects of phenoxybenzamine on nitrous oxide-induced reproductive toxicity in Sprague-Dawley rats.

In previous studies, we have shown that the reproductive toxicity of N2O in rats is prevented by the co-administration of either halothane or isoflurane, whereas treatment with folinic acid, which should reverse the effects of N2O on DNA production, does not prevent toxicity. These results cast doubt on the commonly held theory that inactivation of methionine synthase is the sole cause of N2O-induced reproductive toxicity, and suggest the need for other hypotheses. One such possibility is that N2O causes adverse reproductive toxicity secondary to its sympathomimetic effects. As a first step to test this theory, we studied the effects of phenoxybenzamine (PX), an alpha-1 adrenergic antagonist, on N2O-induced reproductive toxicity using a well-established in vivo rat model. On day 8 of gestation (plug day = day 0), 130 timed-pregnant Sprague-Dawley rats were injected s.c. with either 0.5 ml of either 0.9% saline (control and N2O alone groups) or PX (0.5, 5, or 50 micrograms/kg) in 0.9% saline, the latter the maximum tolerated PX dose. They were then exposed to either air (control) or 60% N2O for 24 hours (all other groups). On day 20 of gestation, cesarean sections were performed and the fetuses were removed and examined for either visceral of skeletal abnormalities. Compared with control, treatment with N2O alone resulted in increased incidences of fetal resorptions, major and minor visceral abnormalities, and minor skeletal abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1991

Adverse interaction between bupivacaine and halothane on ventricular contractile force and intraventricular conduction in the dog.

Regional anesthesia with bupivacaine in pediatric patients is often accompanied by light levels of halothane general anesthesia. To determine the potential cardiotoxicity of these two drugs when used together, we defined the interaction between moderate plasma bupivacaine concentrations (1270-1760 ng/mL) and halothane (end-tidal concentrations, 0.5%-1.0%) on ventricular contractility and conduction in 22 closed-chest dogs anesthetized with chloralose. Bupivacaine alone (1-mg/kg intravenous bolus plus a 0.1-mg.kg-1.min-1 constant rate infusion) resulted in significant increases in ventricular conduction time (VCT) and effective refractory period (VERP) and nonsignificant decreases in dP/dtmax and blood pressure. The addition of halothane resulted in hypotension and in progressively increasing plasma bupivacaine levels secondary to reduced hepatic clearance, which led to further dose-related significant increases in VCT and VERP and to significant decreases in dP/dtmax and blood pressure. In other dogs given halothane but in which bupivacaine levels were held constant (1400 ng/mL), VCT remained constant and VERP lengthened slightly, whereas dP/dtmax decreased. We conclude that the combination of bupivacaine and halothane can cause adverse effects on ventricular contractility and intraventricular conduction.

Anesthesia↗
PubMed1991

Appendectomy during pregnancy: a Swedish registry study of 778 cases.

Data from three Swedish health care registries--the Medical Birth Registry, the Registry of Congenital Malformations, and the Hospital Discharge Registry--were linked for the 9-year period 1973-1981 to identify women who had appendectomy during pregnancy and their offspring, and to determine several pregnancy outcomes (gestational duration, birth weight, perinatal mortality, and congenital anomalies). Among the 720,000 deliveries during this period, 778 were complicated by appendectomy (one in 936), and the diagnosis of appendicitis was confirmed in 64% of the cases (one in 1440). Significant findings included: 1) an increase in the risk of delivery the week after appendectomy when the operation was performed after 23 weeks' gestation, with no further increase if the pregnancy continued beyond 1 week; 2) a decrease in mean birth weight of 78 +/- 24 g with more infants than expected weighing less than 3000 g; 3) an increase in the number of live-born infants dying within 7 days of birth; 4) no increase in the number of stillborn infants; and 5) no increase in the number of congenitally malformed infants.

Adult↗
PubMed1990

Nitrous oxide alters body laterality in rats.

Seventy timed-pregnant Sprague-Dawley rats were exposed to either air (control) or 75% nitrous oxide (N2O) for 24 hours on day 8 of gestation. Four rats from each group were killed on days 11-16, 18, and 20, and laparotomy was performed. The viability of the embryos/fetuses was determined, as was the side of tail flexion on days 11 and 12, the direction from which the umbilical artery emerged from the body on days 13 and 14, the side of the body facing the placenta on days 15 and 16, and the side to which the aortic arch curved on days 18 and 20. Mean mortality rate in the control group was 8.9 +/- 6.1% (+/- S.D.), and there were no control embryos/fetuses with altered laterality except the 9% that faced left on day 16. In contrast, N2O treatment on day 8 of gestation resulted in significantly increased mortality (40.8 +/- 3.3%) beginning on day 14 of gestation and increased incidence of altered laterality overall (31.3%) and at all stages of development. The mechanisms underlying these events remain to be defined, as do the implications of our findings for pregnant surgical patients and occupationally exposed workers.

Animals↗
PubMed1990

Neural tube defects and first trimester operations.

Swedish health care registries were used to identify women who had surgery during pregnancy and their offspring. Among the 2,252 infants born to women who had first trimester operations during 1973-1981, six had definite diagnoses of neural tube defects (expected number, 2.5). Scrutiny of the records showed that 572 operations occurred during gestational weeks 4-5, the period of neural tube formation, and that the mothers of five of the six infants with neural tube defects had an operation during that period (expected number of neural tube defects, 0.6) although one of the offspring probably had Meckel's syndrome. The relationship between neural tube defects and operation during pregnancy is discussed including the possibility that the association may be random.

Abnormalities, Drug-Induced↗
PubMed1979

Mutagenicity of inhalation anaesthetics: trichloroethylene, divinyl ether, nitrous oxide and cyclopropane.

The mutagenic potential of trichloroethylene, divinyl ether, nitrous oxide and cyclopropane was assessed in vitro by microbial assay employing two histidine-dependent strains of Salmonella typhimurium, TA1535 and TA100. Anaesthetic agents in various concentrations were incubated with bacteria in the presence or absence of an enzyme system prepared from enzyme-induced rat liver. Nitrous oxide and cyclopropane were not mutagenic, whereas divinyl ether gave a strongly positive response. Results for trichloroethylene were equivocal. These and previous studies with the salmonella system, together with mutagenicity studies using different test systems, indicate that modern inhalation anaesthetic agents are unlikely to be mutagenic.

Anesthesia, Inhalation↗
PubMed1979

Metabolism of synthane: comparison with in vivo and in vitro defluorination of other halogenated hydrocarbon anaesthetics.

Aerobic defluorination of the inhalation anaesthetic agent, synthane, was compared with that of methoxyflurane, enflurane and halothane and with two other anaesthetics, isoflurane and sevoflurane. In vitro, in microsomes prepared from phenobarbitone-induced and control livers, synthane and halothane were not defluorinated. The relative order of defluorination of the other anaesthetics was methoxyflurane greater than enflurane greater than isoflurane. In vivo, following 4 h of 1.2% (MAC) synthane anaesthesia, urinary inorganic fluoride excretion was increased by only a trivial amount and only in phenobarbitone-treated rats; polyuria was not observed. Synthane is the least metabolized of the fluorinated ether anaesthetics; its administration will not result in inorganic fluoride nephropathy. An index of nephrotoxic potential for fluorinated anaesthetic agents was formulated utilizing in vitro fluoride production data and oil: gas partition coefficients.

Anesthesia, Inhalation↗
PubMed1979

Carcinogenicity of halothane in Swiss/ICR mice.

A simplified in-vivo bioassay system was used to test the carcinogenic potential of halothane in Swiss/ICR mice. Halothane was tested only at its maximum tolerated dose, and histologic examination was performed only on tumor masses and other grossly abnormal tissues found at necropsy. Two groups, each of 15 timed pregnant mice, were exposed to either halothane, 500 ppm (0.05 per cent), or compressed air for two hours on days 10--19 of pregnancy. Five days after birth the offspring were similarly exposed, three times weekly, for 78 weeks. After a ten-week, no-treatment, observation period, all remaining mice were examined by necropsy. Mice dying or killed in extremis before final sacrifice at 88 weeks of age also underwent complete gross necropsy unless extensive cannibalism or autolysis precluded examination. The incidences of malignant tumors, hepatomas or modular hyperplasias, and benign tumors in halothane-treated mice were 7, 6, and 20 per cent, respectively; there were similar incidences of these lesions in control animals. It is concluded that under the conditions of this experiment, lifetime administration of halothane at its maximum tolerated dose is not associated with an increased incidence of neoplasia in Swiss/ICR mice.

Adenoma↗
PubMed1979

Halothane biotransformation in anesthetists.

Serum bromide levels were measured in 115 anesthetists by use of x-ray fluorescence spectrometry. Bromide levels peaked at 184 +/- 21 micron in anesthetists regularly exposed to halothane (n = 20), at 58 +/- 4 micron in anesthetists sporadically exposed to halothane (n = 71), and at 46 +/- 3 micron in nonexposed anesthetists (n = 24). Kinetic studies were carried out in five other anesthetists after ten days of exposure to halothane. Average daily halothane concentration was 19.2 +/- 3.2 ppm; duration of exposure was 3.8 +/- 0.2 hours/day. Mean serum bromide level increased from 40 +/- 4 micron before exposure to 220 +/- 36 micron on the last day of exposure. Serum bromide half-life was 14 +/- 1.7 days. The study demonstrates that anesthetists debrominate halothane in a dose-related fashion. Serum bromide levels achieved, however, were far below those reported to result in clinical bromism.

Anesthesiology↗
PubMed1979

Fetal morphology in mice exposed to halothane.

The teratogenic potential of subanesthetic and anesthetic exposure to halothane was studied in Swiss/ICR mice. Two treatment regimens were employed: daily exposure of males and females for nine weeks prior to conception and on days 1 through 17 of pregnancy; and exposure of females only on days 6 through 15 of pregnancy. Mice were exposed to subanesthetic concentrations of halothane for 0.025, 0.1, 0.4, and 1.2 MAC hours/day; anesthetic exposure was 4.0 MAC hours/day. Fetal morphologic development was normal at the two lowest exposures. Exposures of 0.4 MAC hours/day and more were associated with decreased fetal ossification. At the 1.2 MAC hour/day exposure, renal pelvic masturation was retarded and the incidence of skeletal variants was increased. The incidences of major malformations and minor anomalies were not increased following exposure to subanesthetic concentrations of halothane. Anesthetic exposure to 4.0 MAC hours/day was lethal to both dams and embryos, and resulted in major developmental malformations in surviving fetuses. These effects were probably due to altered maternal physiologic status. It is concluded that exposure of mice to subanesthetic concentrations of halothane does not result in important morphologic abnormalities in their offspring.

Abnormalities, Drug-Induced↗
PubMed1979

Effect of phenytoin (DPH) treatment on methoxyflurane metabolism in rats.

The toxicity and metabolism of the fluorinated anesthetic methoxyflurane were compared in Fischer 344 rats pretreated with phenytoin or phenobarbital. Treatment with either drug potentiated the polyuric effects of methoxyflurane by more than 100%. Also, serum inorganic fluoride (F-) levels and urinary F- excretions after methoxyflurane exposure were comparable in phenytoin- and phenobarbital-treated rats, a 26 to 49% increase as compared to rats treated with methoxyflurane alone. In vitro, 10-fold increases in the rate of hepatic microsomal methoxyflurane defluorination were observed after treatment of rats with either phenytoin or phenobarbital. Kinetic studies with microsomes demonstrated inhibition of methoxyflurane defluorination in the presence of phenytoin. Defluorination of three additional fluorinated ether anesthetics, enflurane, isoflurane and sevoflurane, also was examined in vitro. Phenytoin and phenobarbital treatment resulted in similar enhancement of defluorination of the latter two anesthetics, but not enflurane. Phenytoin and phenobarbital treatment increase defluorination of fluorinated ether anesthetics to approximately the same extent in vitro and in vivo in Fischer 344 rats.

Anesthetics↗
PubMed1979

Renal effects of enflurane anesthesia in Fischer 344 rats with pre-existing renal insufficiency.

Chronic renal insufficiency was produced surgically in Fischer 344 rats in order to evaluate the effects of enflurane anesthesia in animals with impaired renal function. Three groups of rats were anesthetized with enflurane: a control group without impairment of renal function (n = 7); a group with minimal impairment of renal function (n = 6); and a group with moderately severe renal impairment (n = 9). Another group of rats with moderately severe renal impairment (n = 8) was anesthetized with halothane. Two hours of anesthesia resulted only in mild transient depression of urea clearance in all groups. Six hours of anesthesia resulted in a 5 to 10 ml/day increase of urinary output in all groups and small increases in urea nitrogen levels in both groups with moderately severe renal impairment. Deterioration of the model was noted late in the experiment; at sacrifice, animals that had been anesthetized with enflurance and four with halothane had terminal renal failure. The morphological lesion in both groups was similar, resembling glomerulonephritis. Thus, there was no difference in the renal response to enflurane or halothane anesthesia among rats with chronic renal insufficiency.

Animals↗
PubMed1978

Fluroxene mutagenicity.

The commercially available volatile anesthetic fluroxene (2,2,2-trifluoroethyl vinyl ether) which contains the stabilizer N-phenyl-1-napthylamine, was tested for mutagenicity using four strains of S. typhimurium, TA1535, TA1537, TA98 and TA100, and one strain of E. coli, WP2. In addition, purified fluroxene; N-phenyl-1-napthylamine; trifluoroethanol, a major metabolite of fluoroxene; and urine from rats anesthetized with fluroxene were tested. Several procedures were utilized including exposure of bacteria to vapor in desiccators and in liquid suspension. Results indicate that fluroxene, but not its stabilizer, was mutagenic to strains TA1535, TA100 and WP2 only in liquid suspension and only in the presence of a rat-liver enzyme system. Trifluoroethanol and urine from fluroxene-treated rat were not mutagenic to any strain of bacteria. These findings indicate that fluroxene is a promutagen which requires preincubation before it is recognized. Further experiments were performed with enzymes prepared from mouse, hamster and human liver. Fluroxene was mutagenic only in the presence of enzymes prepared from Aroclor 1254 pretreated rodents. Since fluroxene was not mutagenic in the presence of enzymes prepared from three human livers, the significance of these findings to man are unclear.

Animals↗